Akira 1993

ADVANCES IN IMMUNOLOGY, VOL.
54
Interleukin-6 in Biology and Medicine
SHIZUO AKIRA,. TETSUYA TAGA,' AND TADAMITSU K l S H l M O T W
* Institute for Molecular and Cellular Biology, Osaka University, Osaka 565, Japan,
t
and Department of Medicine Ill, Osaka University
Medical School, Osaka 553, Japan
1. Introduction
Interleukin-6 (IL-6) is a cytokine with pleiotropic activities that
plays a central role in host defense (Kishimoto, 1989; Shegal, 1990;
Akira et al., 1990a; Hirano et al., 1990; Van Snick, 1990).IL-6 can exert
growth-inducing, growth-inhibitory, and differentiation-inducing
activities, depending on the target cells. These activities include
(1)terminal differentiation (secretion of immunoglobulins) in B cells,
(2) growth promotion on various B cells (myeloma/plasmacytoma/
hybridoma cells), (3) support of multipotential colony formation by
hematopoietic stem cells, (4) elicitation of hepatic acute-phase re-
sponse, ( 5 ) differentiation and/or activation of T cells and macro-
phages, and (6) neural differentiation. In previous studies this mole-
cule was described with various designations such as B cell
stimulatory factor 2 (BSF-2),interferon-& (IFN-&), hybridoma growth
factor (HGF), and hepatocyte-stimulating factor (HSF).The name IL-6
was proposed because the nucleotide sequences of all these proteins
were found to be identical (Table I). IL-6 has now been implicated in
the pathology of many diseases including multiple myeloma, mesan-
gial proliferative glomerulonephritis, rheumatoid arthritis, and ac-
quired immunodeficiency syndrome (AIDS). Selective inhibition of
the synthesis or of the action of IL-6 may have therapeutic benefit
against the IL-6-associated diseases. On the other hand, IL-6 has
potent antitumor activity against certain types of tumors. Application
of IL-6 is promising in cancer treatment as well as in treatment of
radiation- or chemotherapy-induced myelosuppression.
II. Historical Overview

A. B CELLSTIMULATORYFACTOR 2
On antigenic stimulation, B cells proliferate and differentiate into
antibody-producing cells under the control of T cells and macro-
phages. This process was found to be mediated by soluble factors
1
Copyright 8 1993 hy Academic Press, Inc.
All rights of reproduction in any form reserved.
2 SHIZUO AKIRA ET AL.
TABLE I
FACTORSTHATHAVETURNED OUT TO BE
IDENTICAL TO INTERLEUKIN-6
B cell stimulatory factor-2 (BSF-2)

B cell differentiation factor (BCDF)
Interferon-B2(IFN-&)
26-kDa protein
Hybridoma/plasmacytomagrowth factor
(HPGF)
Interleukin hybridoma plasmacytoma 1
(ILHP-1)
Plasmacytoma growth factor (PCT-GF)
Hepatocyte-stimulating factor (HSF)
Macrophage granulocyte-inducing factor 2
( M G1-2)
Cytotoxic T cell differentiation factor (CDF)
Thrombopoietin
(Dutton et al., 1971; Schimple and Wecker, 1972; Kishimoto and Ishi-
zaka, 1973). In the early 1980s it was shown that at least two different
factors, B cell growth factor (BCGF) and B cell differentiation factor
(BCDF), were involved in the regulation of B cell differentiation (Yo-
shizaki et al., 1982). Since then a variety of factors have been reported
to be involved in the regulation of proliferation and differentiation of B
cells into antibody-producing cells (Kishimoto, 1985). B cell stimula-
tory factor 2 (BSF-2) was identified as a factor in the culture super-
natants of phytohemagglutinin (PHA-stimulated) (Muraguchi et al.,
1981) or antigen-stimulated (Teranishi et al., 1982) peripheral mono-
nuclear cells that induced immunoglobulin (Ig) synthesis in Epstein-
Barr virus (EBV)-transformed B cell lines and was originally called
BCDF. This molecule, BCDF/BSF-2, was separable from other factors
such as IL-2 and BCGF (Yoshizaki et aZ., 1982; Hirano et al., 1984). It
was also demonstrated that BSF-2 functions in the late phase of Staph-
ylococcus aureus Cowan I (SAC)-stimulated normal B cells (Hirano et
al., 1984)or EBV-transformed cells (Yoshizakiet al., 1982)to induce Ig
production, provided other factors such as IL-2 and BCGF are avail-
able. Furthermore, BSF-2 was found to act on B cell lines and augment
the levels of mRNA and protein of secretory-type Ig (Kikutani et al.,
1985). BSF-2 was purified to homogeneity (Hirano et aZ., 1985) from
the culture supernatant of a human T cell leukemia virus type I (HTLV-
1)-transformed T cell line and its partial N-terminal amino acid se-
quence was determined (Hirano et aZ., 1987).On the basis of the amino
INTERLEUKIN-6 I N BIOLOGY AND MEDICINE 3
acid sequence, the corresponding cDNA was cloned from a T cell line
(Hirano et al., 1986).
B. HYBRIDOMA/PLA.SMACYTOMA GROWTHFACTOR
In 1972, Namba and Hanaoka demonstrated that a murine adherent
phagocytic cell line produces a growth factor(s) that promotes the
growth of the MOPC 104E plasmacytoma cell line (Namba and Ha-
naoka, 1972). Growth factors for plasmacytoma were also reported
(Metcalf, 1974; Corbel and Melchers, 1984; Nordan and Potter, 1986).
A growth factor(s) for murine hybridoma was found in supernatants of
human endothelial cells (Astaldi et al., 1980) and human monocytes
(Aarden et al., 1985). A hybridoma growth factor designated interleu-
kin hybridoma plasrnacytoma 1 (IL-HPl) (Van Snick et al., 1986)and a
molecule termed plamacytoma growth factor (PCT-GF) (Nordan et
al., 1987) were purified from a murine helper T cell clone and a murine
macrophage cell line P388D1, respectively, and their partial N-
terminal amino acid sequences were determined, demonstrating that
both growth factors were identical. Human hybridoma/plasmacytoma
growth factor (HPGF) was also purified from an osteosarcoma cell line
MG-63 (Van Damme et al., 1987b) and peripheral blood monocytes
(Brakenhoff et al., 1987). Although the N-terminal amino acid se-
quence of murine HPGF was found to have no homology with that of
human HPGF, molecular cloning of murine IL-HPl demonstrated that
murine HPGF has a sequence homology with the human equivalent
(Van Snick et al., 1988).
c. INTERFERON-&/26-kDa PROTEIN
In 1980, Weissenbach et al. reported that human fibroblasts contain
a novel interferon (IFN) mRNA that is inducible by poly(rI).poly(rC)
and cycloheximide. This mRNA has a different size (1.3kb) and trans-
lation product (26 kDa) from IFN-/3 (Wiessenbach et al., 1980).The
corresponding 26-kDa protein was given the name interferon-&
(IFN-&) because of an antiviral activity that could be inhibited by
antisera against IFN-P. Content et al. (1982) cloned the same mRNA
species but concluded that the 26-kDa protein had no antiviral activity
and was not serologically related to IFN-p. The 26-kDa protein was
shown to be induced in fibroblasts on stimulation with IL-1 (Content et
al., 1985; Van Damme et al., 1985).The nucleotide sequences of the
cDNAs encoding human IFN-& and the 26-kDa protein were deter-
mined and showed the identity of these molecules (Zilberstein et al.,
1986; Haegemann et al., 1986).
D. HEPATOCYTE-STIMULATING
FACTOR
Acute inflammation is accompanied by changes in many plasma
protein concentrations. As the acute-phase proteins are synthesized in
the liver and injury to another part of the body results in increased
synthesis of acute-phase proteins, the existence of hormone-like medi-
ators was proposed. The isolation and characterization of a regulatory
molecule(s) controlling plasma protein biosynthesis have been a major
interest in several laboratories for the past two decades. Substances in
the leukocyte extracts were found to drastically change the concentra-
tion of certain plasma proteins produced by hepatocytes. The leuko-
cyte product was named hepatocyte-stimulating factor (HSF) by sev-
eral groups. Gauldie et al. (1987) as well as Andus et al. (1987)
demonstrated that HSF is identical to the cytokine known as IFN-&,
BSF-2, or HPGF.
111. Structure and Expression of Interleukin-6

A. STRUCTURE
Interleukin-6 is a glycoprotein with a molecular mass in the range 20
to 30 kDa, depending on the cellular source and preparation. The
molecular weight heterogeneity of IL-6 results from post-translational
modifications such as N- and 0-linked glycosylation and phosphoryla-
tion (May et al., 1988a,b); however, these differences in molecular size
do not seem to play a major role in the biological activities of IL-6.
cDNAs encoding human, murine, and rat IL-6 have been cloned.
Human IL-6 (Hirano et al., 1986)consists of 212 amino acids including
a 28-amino-acid signal peptide, whereas mouse (Van Snick et al., 1988)
and rat (Northemann et al., 1989) IL-6 consist of 211 amino acids with
a 24-amino-acid signal sequence. Comparison of the cDNA sequence
of mouse IL-6 with that of human IL-6 shows a homology of 65% at the
DNA level and 42% at the amino acid level, although the murine and
rat protein sequences are 93% identical. Despite the low amino acid
homology between human IL-6 and its murine counterpart, human
IL-6 works on murine cells with the same biological activity as mouse
IL-6, but not vice versa. There is very little homology in the N-terminal
region, but the central portion is more conserved (57% for the region
spanning residues 42-102). In particular, the four cysteine residues of
the protein, which are located in this region, can be perfectly aligned.
The same motif of four cysteines is also found in human and mouse
granulocyte colony-stimulating factor (G-CSF) and in chicken myelo-
monocytic growth factor (MGF), suggesting an evolutionary relation
INTERLEUKIN-6 IN BIOLOGY AND MEDICINE 5
between these molecules (Leutz et al., 1989). The two disulfide

bridges in mouse IL-6 have been located between Cys 46-Cys 52 and
Cys 75-Cys 85 (Simpson et al., 1988). With the exception of the short
segment (amino acids 1-28) at the N terminus, the entire primary
sequence of human IL-6 is shown to be required for biological activity
(Brakenhoff et al., 1989; Kriittgen et al., 1990; Snouwaert et d.,
1991).
IL-6 is predicted to have a common tertiary fold similar to the four-a-
helix bundle structure found in growth hormone, despite little similar-
ity in amino acid sequence (Bazan, 1990a, b) (Fig. 1).The evolutionary
relationship between G-CSF and 1L-6 is cemented by a common pat-
tern of exons and introns in their respective genes. The predicted
helices (labeled A to D) and loops (two long A-B and C-D loops, one
short B-C loop) map to distinctive exon-encoded parts of the aligned
chains. Other cytokines including G-CSF, MGF, prolactin (PRL), and
erythropoietin (EPO) adopt the similar helical fold-and-loop topology.
The region of greatest similarity between these molecules lies at the
C-terminal end (helix D) of the alignment of protein chains. Muta-
genetic, deletion, and neutralizing antibody studies for PRL, EPO,
IL-6, and G-CSF suggest that the surface of predicted helix D is the
primary receptor-binding structure.
FIG.1. Schematic ternary structure of interleukin-6. IL-6 protein is predicted to be

composed of four (I helices (A through D) and loops connecting them.
B. INDUCERS AND PRODUCERS
Interleukin-6 is produced by many different cell types including

monocytes/macrophages, fibroblasts, keratinocytes, endothelial cells,
mesangial cells, glial cells, chondrocytes, osteoblasts, smooth muscle
cells, T cells, B cells, granulocytes, mast cells, and certain tumor cells
(Table 11). Constitutive IL-6 production is reported in a number of
tumor cell lines such as cardiac myxoma, cervical carcinoma, renal
carcinoma, and bladder carcinoma cells. Except for tumor cells that
produce IL-6 constitutively, normal cells do not produce IL-6 unless
appropriately stimulated. The production of IL-6 is positively or nega-
tively regulated by a variety of stimuli. Such positive and negative
TABLE I1
CELL SOURCES AND INDUCERS OF INTERLEUKIN-6
Cell Type Inducer

Fibroblasts IL-1, TNF, PDGF, IFN-p, LPS, viruses, serum,
poly(I).poly(C), adenyl cyclase activators (forskolin,
cholera toxin, isobutylmethylxanthine, dibutylyl
CAMP),calcium ionophore A-23187, cycloheximide,
PMA, diacylglycerol, prostaglandin E l , sodium
fluoride, ouabain
Monocyte/macrophage LPS, IL-6, IFN-7, PMA, GM-CSF, IL-I, CSF-1, viruses
(HIV), adherence, muramyl dipeptide(MDP), C5a
Endothelial cells LPS, IFNy, IL-I, TNF, IL-4
Keratinocytes IL-1, PMA, LPS, Con A, UV irradiation, IL-4
Endometrial stromal cells IL-1, TNF, IFN-7
Bone marrow stromal IL-1, IL-6
cells
B cells Staphylococcus aureus Cowan I, IL-4, IL-1, TFN-a
T cells PHA + TPA, PHA + monocyte, anti-CD3 antibody,
HTLV infection
Mast cells Antigen + IgE, PMA, Con A, calcium ionophore A-23187
Neutrophils GM-CSF, TNF
Osteoblasts IL-I, TNF, LPS, bradykinin, parathyroid hormone
Astrocytes IL-1, TNF, LPS, calcium ionophore A-23187
Kupffer cells LPS, IL-1, TNF
Intestinal epithelial cells TGF-/3
Vascular smooth muscle IL-1
cells
Anterior pituitary cells PMA, LPS, vasoactive intestinal peptide(VIP), IL-1
Adrenal gland cells IL-1, protein kinase C activators, LPS, calcium ionophore
A-23187, prostaglandin Ez, forskolin, dibutylyl CAMP,
angiotensin 11, ACTH
Myocytes Serum, calcium ionophore, A-23187
regulation of IL-6 production varies, depending on the cell type. Lipo-

polysaccharide (LPS) enhances IL-6 production in monocytes and
fibroblasts (Helfgott et al., 1987). Various viruses induce IL-6 produc-
tion in fibroblasts (Sehgal et al., 1988; Van Damme et al., 1989) or in
the central nervous system (Frei et al., 1988). A variety of peptide
factors, such as IL-1, tumor necrosis factor (TNF), IFN-P, and platelet-
derived growth factor (PDGF) enhance IL-6 production in fibroblasts
and certain tumor cell lines (Kohase et al., 1986; Walther et al., 1988,
Van Damme et al., 1987a). Interferon-y (IFN-y) induces IL-6 produc-
tion by macrophages and endothelial cells (Leeuwenberg et al., 1990;
Sanceau et al., 1989). IL-6 does not induce IL-1 or TNF. Rather, IL-6
suppresses endotoxin-induced IL-1 and TNF production (Aderka et
al., 1989; Schindler et al., 1990). Moreover, in certain conditions IL-6
is capable of inducing its own production (Shabo et al., 1989; Miyaura
et al., 1989). IL-4 is a potent inducer of IL-6 production in normal B
cells, keratinocytes, and endothelial cells (Smeland et al., 1989;
Howell et al., 1991, Colottia et al., 1991), whereas IL-4 inhibits IL-6
production in monocytes, fibroblasts, and synoviocytes (te Velde et al.,
1990; Gibbons et al., 1990; Cheung et al., 1990; Lee et al., 1990;
Miossec et al., 1992). Tumor growth factor (TGFP) downregulates
IL-6 production by human monocytes (Musso et al., 1990), but it en-
hances IL-6 production by intestinal epithelial cells (McGee et al.,
1992). IL-10 inhibits the production of IL-6 by macrophages (Fioren-
tino et al., 1991; de Waal Malefyt et al., 1991). Thus, the multiple
interactions between cytokines (cytokine network) exist for the regula-
tion of IL-6 production. Second-messenger agonists such as diacyl-
gycerol, phorbol ester, forskolin, isobutylmethy/xanthine, and calcium
ionophore A-23187 also stimulate IL-6 gene expression (Sehgal et al.,
1987a; Zhang et al., 1988).
At least two signal pathways are involved in IL-6 induction by IL-1
or TNF, one requiring protein kinase C (PKC) activation (Sehgal et al.,
1987a) and the other involving adenylate cyclase (Zhang et al., 1988);
however, these two mechanisms, singly or in combination, cannot
completely account for IL-6 induction by TNF or IL-1, suggesting that
other, as yet unidentified signal transduction mechanisms also play a
role in IL-6 induction by these cytokines.
Production of IL-6 can be further superinduced by cycloheximide
treatment, suggesting that regulation of production of these cytokines
is under the control of labile repressor proteins. Dexamethasone and
other glucocorticoids can markedly suppress the production of IL-6
(Helfgott et al., 1987). This suppression is shown to occur at both the
transcriptional and the post-transcriptional levels. IL-6 contains re-
peating AU-rich sequences in its 3' untranslated region, which are

commonly observed in the 3'untranslated regions of mRNAs for lym-
phokines, cytokines, and proto-oncogenes, and thought to be involved
in mRNA stability (Shaw and Kamen, 1986).These AU-rich sequences
may act to confer cycloheximide superinduction or dexamethasone
suppression. 17P-Estradiol also inhibits IL-6 gene expression in endo-
metrial stromal cells (Tabibzadeh et al., 1989).
c. REGULATIONOF INTERLEUKIN-6 GENEEXPRESSION
The chromosomal genes for human and murine IL-6 were isolated
(Yasukawa et al., 1987; Tanabe et al., 1988).The complete human and
mouse IL-6 genes are approximately 5 and 7 kb long, respectively and
both consist of five exons and four introns. The gene organization of
IL-6 is very similar to that of G-CSF, suggesting that these genes might
have evolved from a common ancestor. The genes for human and
mouse IL-6 are located on the short arm of chromosome 7 ( 7 ~ 2 1and )
the proximal region of chromosome 5, respectively (Sehgal et al.,
1987b; Ferguson-Smith et al., 1988; Mock et al., 1989). There is con-
siderable polymorphism in the human IL-6 gene; three MspI, two
BglII, and at least four BstNI alleles that segregate independently
have been identified by restriction fragment length polymorphism
(Bowcock et al., 1988). Thus, theoretically, there exist up to 24 differ-
ent IL-6 haplotypes in the human population. The MspI and BglII
alleles represent point mutations in introns within the IL-6 gene,
whereas the BstNI alleles represent high-frequency insertion/deletion
events occurring on the 3' side of the IL-6 gene; however, none of the
polymorphisms appears to affect the structure of IL-6 mRNA or its
translation product.
The region extending -350 bp upstream of the transcriptional start
is highly homologous between human and mouse IL-6 genomic genes
(Tanabe et al., 1988). Potential transcriptional control elements are
identified within the conserved region of the IL-6 promoter, as indi-
cated in Fig. 2. Isshiki et al. (1990) showed that the -180 to -122 region
in the IL-6 promoter is involved in IL-1 induction. They also identified
a nuclear factor, termed NF-ZL6, binding to a 14-bp nucleotide
(ACATTGCACAATCT)within the IL-1-responsive element. Ray et al.
(1989) showed that a 23-bp IL-6 multiresponse element (MRE) (-173
to -151)is responsible for induction by IL-1, TNF, and serum as well
as by the activators of protein kinase A (forskolin) and protein kinase C
(phorbol ester). They also identified several sequence-specific com-
plexes that were increased in intensity in HeLa cell nuclear extracts
after stimulation. In this region, a CRE motif as well as an upper half of
NF-IL6 NF-KB
-173 MRE (Bindingrite) - 1 6 -73 (Binding site) -64
GCTAAAGGACGT~CA~GCACAATCT~ GCA"CC4
GRE GRE AP-1 CRENF-IL6 C-fOERCE N F - a TATA

c-fos SRE homology homology
FIG.2. Transcriptional regulatory elements identified in the human interleukin-6
promoter. c-fos SRE homology represents a 70%nucleotide sequence identity across a
50-nucleotide stretch of the c-Jos enhancer, including the SRE (serum response ele-
ment). GRE, glucocorticoid response element; CRE, cyclic AMP response element;
AP-1, activation protein 1; RCE, retinoblastoma control element; MRE, multiresponse
element.
the 14-bp palindrome are present. An NF-KB binding motif is also

present at position -73/-64. Several groups demonstrated that NF-KBis
responsible for IL-6 induction (Shimizu et al., 1990; Liberman and
Baltimore, 1990; Zhang et al., 1990). Thus, three regulatory regions
have been shown to be involved in regulation ofthe IL-6 gene (Fig. 2).
1. NF-IL6
NF-IL6 was initially identified as a nuclear factor binding to a 14-bp
palindromic sequence (ACATTGCACAATCT) within an IL-1-
responsive element in the human IL-6 gene (Isshiki et al., 1990). The
gene encoding NF-IL6 was cloned from a Xgtll cDNA expression
library of LPS-stimulated human peripheral monocytes by a south-
western method (Akira et aZ., 1990b). The cloned NF-IL6 contained a
region highly homologous to the C-terminal portion of C/EBP, the first
nuclear factor proposed to contain a leucine zipper structure (Lands-
chulz et aZ., 1988a,b). The highly homologous region includes a basic
domain and a leucine zipper structure essential for DNA binding and
dimerization, respectively. NF-IL6 recognizes the same nucleotide
sequences as C/EBP. Both proteins recognize a variety of divergent
nucleotide sequences with different affinities, and the consensus se-
quence is T(T/G)NNGNNAA(T/G).Expression of these two proteins
is, however, quite different. C/EBP is expressed in liver and adipose
tissues and is supposed to regulate several hepatocyte- and adipocyte-
specific genes. By contrast, NF-IL6 is expressed at an undetectable or
minor level in all normal tissues, but is drastically induced by stimula-
tion of LPS, IL-1, TNF, or IL-6. NF-IL6 can bind to the regulatory
region of various genes including IL-8, G-CSF, IL-1, immunoglobulin,
and acute-phase protein genes (Natsuka et al., 1992).NF-IL6 has been

shown to be identical to IL-GDBP, the DNA-binding protein responsi-
ble for IL-6-mediated induction of several acute-phase proteins (Poli
et al., 1990b). These results indicate that NF-IL6 may be a pleiotropic
mediator of many inducible genes involved in acute-phase, immune
and inflammatory responses (Akira and Kishimoto, 1992).
2 . NF-KB
NF-KBwas originally characterized as a kappa immunoglobulin en-
hancer DNA-binding protein. Binding sites for NF-KBare present in
the regulatory regions of certain cytokine genes (including the TNF,
lymphotoxin, IL-6, IL-8, and P-IFN genes), the IL-2 receptor gene,
class I and I1 histocompatibility antigen genes, several acute-phase
response genes, and several viral enhancers including human immu-
nodeficiency virus type 1 (HIV-1) (Lenardo and Baltimore, 1989).
NF-KB is a complex of two proteins of 50 and 65 kDa. NF-KB preexists
in the cytoplasm of most cells in an inactive form, complexed to IKB.
Stimulation by a number of agents such as phorbol ester, LPS, and
TNF results in the dissociation of the IKB-NF-KB complex, probably
by phosphorylation of IKB. Subsequently the NF-KB heterodimer mi-
grates to the nucleus, where it binds to its cognate DNA binding sites
and activates transcription. The genes encoding the p50 and the p65
subunits of NF-KB were cloned and found to be highly homologous to
the proto-oncogene c-re1 and the Drosophila maternal effect gene
dorsal within a large domain required for DNA binding and dimeri-
zation (Kieran et al., 1990; Gohsh et al., 1990; Nolan et al., 1991).
D. REPRESSIONOF INTERLEUKIN-6 EXPRESSION
It is well known that glucocorticoids have an inhibitory effect on the
production of many cytokines including IL-6, TNF, and IL-1. Ray et al.
(1991) have investigated the molecular basis for the repression of the
IL-6 promoter by the glucocorticoid dexamethasone. The results
showed that the activated GR binds to the inducible enhancers (MRE
and NF-IL6 binding sites) as well as to the basal transcription regula-
tory regions (TATA box and RNA start sites) in the IL-6 promoter, and
its binding interferes with the binding of positive-acting inducible and
basal transcription factors, resulting in the highly efficient repression
of this gene by dexamethasone.
It has recently been shown that wild-type (wt) p53 or wt RB can
repress the IL-6 promoters in serum-induced HeLa cells by CAT
assay, suggesting that p53 and RB may be involved as transcriptional
repressors in IL-6 gene expression (Santhanam et al., 1991b). p53 and
RB are considered to be tumor suppressor proteins that are frequently

mutated in a variety of neoplasms. Increased IL-6 production is
demonstrated in neoplastic cells that exhibit mutations in p53 and RB.
The molecular mechanism underlying p53- or RB-mediated re-
pression of the IL-6 promoter awaits further investigation. c-fos re-
pression by RB was shown to be mediated through a cis-acting element
in the c-fos promoter called the retinoblastoma control element
(RCE)(Robbins et al., 1990).In this respect it is of interest that a region
highly homologous to the RCE is also present between positions -126
and -101 in the IL-6 promoter (see Fig. 2). Furthermore, a variety of
viral proteins including SV40 large T antigen, adenovirus E1B protein,
and human papillomavirus proteins interact avidly with p53 and RB.
In cells transformed or infected with adenovirus or SV40, the trans-
forming proteins of these viruses form physical complexes with p53 or
RB protein, which may inactivate the normal regulatory function of
p53 or RB protein. At the same time, this inactivation of p53 or RB
protein may lead to enhanced or dysregulated production of IL-6.
IV. Interleukin-6 Receptor

A. INTERLEUKIN-6 RECEPTOR
COMPLEX
Human interleukin-6 receptor (IL-6R) cDNA was cloned by use of
the COS7 cell expression system (Yamasaki et al., 1988).On the basis
of the deduced amino acid sequence, human IL-6R consists of an
extracellular region of 339 amino acids, a membrane-spanning region
of 28 amino acids, and a cytoplasmic region of 82 amino acids. Human
IL-GR as well as its mouse and rat homologs cloned by cross-
hybridization has a domain of about 90 amino acids, in the amino
terminus of the extracellular region, which fulfills the criteria for the
constant 2 (C2) set of the immunoglobulin supergene family (Yamasaki
et al., 1988; Sugita et al., 1990; Baumann et al., 1990).The remaining
extracellular region of IL-6R was found to share structural similarity
with subsequently cloned several receptors for, especially, hemato-
poietic cytokines (Bazan, 1990a,b). This finding has defined a hemato-
poietic cytokine receptor family that includes such receptors as IL-2R
(p and y chains), IL-3R, IL4R, IL-5R, IL-GR, IL-7R7 IL-9R, EPO-R,
G-CSF-R, GM-CSF-R, and LIF-R (Bazan, 1990a,b; Taga and Kishi-
moto, 1992; and references therein). They share an approximately
200-amino-acid-homologous module, which is characterized by four
conserved cysteine residues distributed in the amino-terminal half and
a Tip-Ser-X-Trp-Ser (WSXWS in one-letter symbols) motif located
at the carboxyl-terminal end. This homologous module comprises two

tandemly placed fibronectin type I11 domains which often appear in
proteins functioning in cell-to-cell adhesion, implying that the mem-
bers of the hematopoietic cytokine receptor family might have
emerged from a cell surface molecule that could have been involved in
communication between cells via direct contact (Bazan, 1990b; Patthy,
1990). Each of these two fibronectin type I11 domains is composed of
seven folds ofp strands positioned antiparallely so as to form a “barrel-
like” shape (Fig. 3). A trough formed between two “barrels” is be-
lieved to function as a ligand-binding pocket. In fact, in uitro-mutated
IL-6R protein lacking the immunoglobulin-like domain but not the
0 immunoglobulin-
like domain 0 type 111 domain
tibronectin U
FIG.3. Structure ofthe interleukin-6 receptor and gp130. The extracellular region of
IL-6R comprises the immunoglobulin-like domain and the cytokine receptor family
module which is composed oftwo fibronectin type 111 domains. The extracellular region
of gp130 comprises six fibronectin type 111 domains, the second and the third of which
constitute the cytokine receptor family module. The schematic ternary structure of the
cytokine receptor family module is depicted on the left. Amino acid residues are indi-
cated in one-letter codes.
cytokine receptor family module in its extracellular region retains IL-6

binding capability, and according to the predicted ternary structure of
the cytokine receptor family module, many of the amino acid residues
critical for IL-6 binding are distributed to the hinge region between
the two barrel-like fibronectin type I11 domains (Yawata et al., 1993).
The WSXWS motif characteristic of the family is predicted to be in this
hinge region. All the IL-6R mutants possessing amino acid substi-
tutions in either of the four cysteine residues or the WSXWS motif
conserved in the family lack IL-6 binding capability.
The cytoplasmic region of IL-6R is relatively short and has no obvi-
ous catalytic domain, and deletion of this region did not affect the
cellular responsiveness to IL-6. This suggested a receptor component
that is associated with IL-6R and is responsible for signal transduction.
Such a molecule, now called gp130 because it is a 130-kDa glyco-
protein, was discovered by immunoprecipitation of IL-6R protein;
gp130 was co-immunoprecipitated with 1L-6R from digitonin lysates
of IL-6-stimulated cells (Taga et al., 1989). The IL-6 triggered associa-
tion of IL-6R and gp130 takes place at 37°C within 5 minutes but not at
WC, suggesting a requirement for membrane fluidity in this step. The
association of the two membrane proteins is revealed to occur between
their extracellular regions, because the extracellular soluble form of
IL-6R associates with gp130 in the presence of IL-6.
Based on the amino acid sequence deduced from the cDNA cloned
by immunoscreening of an Escherichia coli expression library, human
gp130 is predicted to consist of an extracellular region of 597 amino
acids, a membrane-spanning region of 22 amino acids, and a cytoplas-
mic region of 277 amino acids (Hibi et al., 1990).The entire extracellu-
lar region of human as well as subsequently cloned mouse gp130
comprises six repeats of the fibronectin type I11 domain. Among these
repeats, the second and third type I11 domains compose the hemato-
poietic cytokine receptor family module, possessing the characteristic
four cysteine residues in the former and the WSXWS motif in the latter
(see Fig. 3). It has been demonstrated that despite its lack of IL-6
binding property, gp130 is involved in the formation of high-affinity
binding sites and is critical for IL-6 signal transduction (Hibi et al.,
1990; Taga et al., 1992): (1) cDNA-expressed IL-6R shows only low-
affinity IL-6 binding property, but coexpression of IL6-R with gp130
confers both high- and low-affinity binding sites. (2)Anti-gpl30 mono-
clonal antibody blocks the formation of high- but not low-affinity IL-6
binding sites and also inhibits IL-6-induced biological responses.
(3)The IL-WsIL-GR complex induces DNA synthesis in a transfectant
expressing gp130, but not in its parental pro-B cell line. In conclusion,
14 SHIZUO AKIFU ET AL.
the IL-6R complex comprises two functionally different membrane

proteins: a ligand-binding chain (80-kDa IL-6R) and a nonbinding but
signal-transducing chain (gp130). When IL-6R is occupied by IL-6,
these two chains associate extracellularly to form the high-affinity
functional receDtor.
The signal-transducing chain of the IL-6R complex, that is, gp130,
has been shown to be expressed in nearly all human and mouse cell
lines examined (Hibi et al., 1990; Saito et al., 1992). In the case of the
mouse, such tissues as brain, thymus, heart, lung, spleen, liver, and
kidney are shown to express gp130. As for expression of IL-6R,
although it is also widely distributed in accordance with the pleiotro-
pic nature of IL-6, it does not seem to be as ubiquitous as gp130. In
mouse and human peripheral blood mononuclear cells, monocytes and
T cells (both CD4’ and CD8+ subpopulations) express IL-GR as de-
tected by flow cytometric analysis and binding assay (Taga et al., 1987;
Coulie et al., 1989; Bauer et al., 1989; Hirata et al., 1989). IL-6R is
barely detectable on freshly isolated mouse thymocytes, but appears
after thymocytes are cultured in vitro for 2 days (Coulie et al., 1989;
Kobayashi et al., 1992). B cells do not usually express IL-6R, but they
come to express IL-6R when stimulated in vitro with mitogen (Taga et
al., 1987; Hirata et al., 1989). Peyer’s patch B cells, many of which are
class-switched (to IgA) and considered to be at a more differentiated
stage, express IL-6R before in vitro activation (Fujihashi et al., 1991;
Kobayashi et al., 1992). These findings may reflect the functional dif-
ference of IL-6 in these cells: IL-6 induces (1)differentiation of macro-
phages (Shabo et al., 1988; Miyaura et al., 1988), (2) production of
immunoglobulins in activated but not resting B cells (Muraguchi et al.,
1988; Fujihashi et al., 1991), and (3)proliferation of peripheral T cells
or mitogen-cocultured thymocytes (Garman et al., 1987; Lotz et al.,
1988). In inflammatory contexts, hepatocytes produce acute-phase
proteins, the process of which involves IL-6. IL-GR transcripts ex-
pressed in hepatocytes are increased when the mice are inoculated
with complete Freund’s adjuvant or turpentine (Baumann et al., 1990;
Nesbitt and Fuller, 1992). Under inflammatory conditions, in addition
to IL-6, glucocorticoid is upregulated as a consequence of activation of
the pituitary-adrenal axis. Recombinant IL-6 as well as synthetic glu-
cocorticoid, dexamethasone, enhances IL-6R expression in hepato-
cytes and hepatoma cells (Bauer et al., 1989; Nesbitt and Fuller, 1992;
Rose-John et al., 1990; Saito et al., 1992). As for the level of gp130
transcripts in hepatocytes, although it is indeed upregulated by the
addition of turpentine, IL-6, or dexamethasone, the extent of upregu-
lation is relatively small, or gp130 expression remains rather stable,
compared with the IL-6R levels (Nesbitt and Fuller, 1992; Schooltinck
et al., 1992; Snyers and Content, 1992). These results suggest that
under inflammatory conditions, hepatocytes become more sensitive to
IL-6 to produce acute-phase proteins by upregulating the levels of
receptor components, especially that of IL-6R rather than gp130. The
preceding observations of regulated expression of IL-6R and ubiqui-
tous expression of gp130 suggest that the functions of the pleiotropic
cytokine IL-6 may be controlled by expression of the ligand-binding
chain but not the signal-transducing chain of the receptor complex.
In this context, a case of dysregulated expression found in a plasma-
cytoma cell line has to be noted. In the P3U1 plasmacytoma cell line
the cDNA encoding rearranged IL-6R was isolated; a DNA segment
corresponding to the cytoplasmic region was replaced with part of the
long terminal repeat (LTR)of the intracysternal A-particle gene (Sugita
et al., 1990).The rearranged mouse IL-6R retains the ability to mediate
IL-6 signals, and this rearranged, but functionally normal, IL-6R is
overexpressed in P3U1 cells, probably because of the internal en-
hancer in the LTR sequence. As IL-6 is a potent growth factor for
plasmacytomas, this suggests that overexpression of rearranged IL-6R
might be responsible for the development of this particular plasmacy-
toma cell line. In MRL/lpr autoimmune mice, splenic B cells express
abnormally high levels of IL-6R without any in uitro stimulation,
suggesting its contribution to B cell hyperreactivity in this strain (Ko-
bayashi et al., 1992).
B. SIGNALS THROUGH gp130, WHICHIs S H A R E D BY
SEVERAL CYTOKINES
Since the finding of the IL-6R-associated signal transducer gp130, it
has been hypothesized that functional redundancy, a characteristic
feature of the actions of many cytokines, could be explained if several
different cytokine receptors were to interact with a common signal-
transducing component, such as gp130. Leukemia-inhibitory factor
(LIF)and oncostatin M (OM)were initially identified as growth inhibi-
tors for a mouse myeloid leukemia cell line and human melanoma cell
line, respectively. LIF and OM are multifunctional cytokines whose
biological functions overlap each other and those of IL6, for example,
induction of acute-phase protein synthesis in hepatocytes and macro-
phage differentiation of M 1 cells (Hilton and Gough, 1991; Rose and
Bruce, 1991; Kishimoto et al., 1992). Although LIF-responding cells
express both high- and low-affinity LIF binding sites, cDNA-
expressed LIF-R protein on COS cells shows only low-affinity LIF
binding property, suggesting an additional high-affinity converting
subunit of the LIF-R complex (Gearing et al., 1991). This converter

was later revealed to be identical to the IL-6 signal transducer, gp130;
coexpression of the cDNAs for LIF-R and gp130 was shown to gener-
ate high- and low-affinity LIF binding sites (Gearing et al., 1992). In
addition, although gp130 or LIF-R binds OM with low or null, respec-
tively, intrinsic affinity, coexpression of the two proteins confers
intermediate-affinity OM binding sites, suggesting gp130 and LIF-R
also associate to form an OM-R complex; however, because some
OM-responsive cell lines that express high- and low-affinity OM bind-
ing sites do not express LIF-R, an unidentified receptor component for
the OM-R complex is also suggested (Gearing and Bruce, 1992). Anti-
gp130 monoclonal antibodies completely block the acute-phase
protein synthesis in hepatoma cells induced by either IL-6, LIF, or
OM, and the growth inhibition of melanoma cells induced by either
IL-6 or OM (Liu et al., 1992; Taga et al., 1992). Furthermore, any of
these cytokines rapidly induces tyrosine phosphorylation of gp130 (Ip
et al., 1992; Taga et al., 1992). The results confirmed that gp130 is
critical for the signaling process triggered by these three cytokines.
Among the three cytokines, LIF also shows pleiotropic functions
within the neural system which are overlapped by the functions of
ciliary neurotrophic factor (CNTF), for example, promotion of the sur-
vival of sensory and motor neurons and induction of switch from
adrenergic to cholinergic phenotype in cultured neurons (Yamamori et
al., 1989; Stockli et al., 1989; Kishimoto et al., 1992). Based on the
information from the cloned cDNA, CNTF-R shows the highest se-
quence homology to IL-6R. It lacks transmembrane and cytoplasmic
regions, but is instead anchored to the membrane via a glycosyl-
phosphatidylinositol (GPI)linkage (Davis et al., 1991).These observa-
tions suggest that gp130 may also be associated with CNTF-R. CNTF
actions on neuronal cells were completely blocked by anti-gpl30 anti-
bodies, indicating that CNTF signaling processes involve gp130 (Ip et
al., 1992; Taga et al., 1992). CNTF stimulation rapidly induces ty-
rosine phosphorylation of both gp130 and gpl30-associated 190-kDa
protein. This 190-kDa protein is most likely LIF-R, suggesting that the
functional CNTF-R complex may include LIF-R in addition to gp130
and CNTF-R (Fig. 4).
Interleukin-11 exerts multiple biological functions similar to those
of IL-6, implying that similar signaling processes may be operating in
the IL-6 and IL-11 systems (Baumann and Schendel, 1992).Although a
specific receptor for IL-11 has not yet been molecularly cloned, anti-gp
130 monoclonal antibodies (mAbs) inhibited IL-ll-induced TF-1 cell
proliferation, suggesting that gp130 is essential for 1L-11 signal trans-
FIG.4. Receptor complexes for interleukin-6 (A), CNTF (B), LIF (C),and OM (D).A
signal transducing component, gp130, is shared by these receptor complexes and is
essential for initiating their respective cytoplasmic signaling processes. Cytokine stimu-
lation induces oligomerization of the receptor components which is postulated to
stabilize interaction with a downstream molecule. See text for details.
duction and may be a component of the IL-11R complex (Y.-C. Yang et

al., unpublished).
It should be noted that although the ubiquitously expressed gp130 is
involved in mediating signals elicited by all the previously mentioned
cytokines, the ability of a cell to respond to each of these factors
appears to be regulated by the specific expression of distinct receptor
chains. This may explain why these cytokines with overlapping bio-
logical functions do show their own specific activities as well.
No enzymatic activities or sequence motifs known for signal trans-

duction have been found in gp130 protein; however, a series of studies
have provided clues to understanding how gp130 initiates a cascade of
cytoplasmic signals. Stimulation of cells by either IL-6, LIF, OM,
CNTF, or IL-11 has been shown to induce tyrosine-specific phos-
phorylation of cellular proteins including gp130 (Nakajima and Wall,
1991; Murakami et al., 1991; Yin et al., 1992; Schieven et al., 1992;
Taga et al., 1992).The addition of tyrosine kinase inhibitors blocks cellular
responses induced by IL-6 (Nakajimaand Wall, 1991).Furthermore, stimu-
lated gp130 has been shown to be associated with tyrosine kinase activity,
suggesting that tyrosine kinase may be associated with a130 on stimula-
tion. Stimulation of the cells with IL-6 induces the formation of gp130
homodimers (M. Murakami et al., unpublished). Thus, dimerization of
gp130 may form divalent contact surfaces important for stable interac-
tion with a cytoplasmic molecule such as a tyrosine kinase (see Fig. 4).
At present, it remains unclear exactly what sort of tyrosine kinase
interacts with gp130. As gp130 has been shown to be essential for
transduction of the IL-6, LIF, OM, CNTF, and IL-11 signals, it is
necessary to examine whether the gp130 molecule in each of the
receptor complexes for these cytokines interacts with the same or a
different kinase. In the 277-amino-acid cytoplasmic region of gp130, a
-60-amino-acid portion, proximal to the transmembrane domain, was
shown to be essential for at least IL-6-induced DNA synthesis in a
mouse pro-B cell line (Murakami et al., 1991). In this critical cytoplas-
mic region, two short stretches of amino acids exist that are highly
conserved among many receptors or signal transducers belonging to
the hematopoietic cytokine receptor family, suggesting that a similar
mechanism might be involved in the signaling processes of various
cytokines. A candidate signaling process that operates downstream of
the tyrosine kinase step is protein serinehhreonine phosphorylation.
Serine/threonine kinase inhibitors block IL-6-mediated cellular
responses without affecting IL-6-induced tyrosine phosphorylation
(Nakajima and Wall, 1991). Another candidate molecule functioning
downstream of the putative tyrosine kinase is the p21 Ras protein, In
PC12 cells, formation of GTP-bound Ras is considered to be essential
for their neural differentiation (Szeberenyi et al., 1990). The GTP-
bound form of p21 Ras (activated Ras) is upregulated on stimulation of
PC12 cells by IL-6. A tyrosine kinase inhibitor was observed to block
the IL-6-induced formation of GTP-bound Ras (Nakafuku et al., 1992).
With respect to the involvement of serinelthreonine kinase and Ras in
IL-6 signal transduction, a recent finding on a nuclear factor, NF-IL6,
has provided a clue to the better understanding of the pathway from
receptor to nuclear factor, an ultimate target of the IL-6 signal. NF-IL6

was originally identified as a sequence-specific nuclear factor involved
in IL-l-induced IL-6 gene expression (Akira et at., 1990b).NF-IL6 was
subsequently found to interact with an IL-6-responsive element in the
promoters of acute-phase protein genes whose expression in liver is
regulated by IL-6. Thus, IL-6-induced activation of acute-phase genes
in hepatocytes may be controlled by modification of NF-IL6. Serine-
and threonine-specific phosphorylation of NF-IL6 has been demon-
strated to be critical for its activation. Involvement of a serine/
threonine kinase such as MAP kinase in this phosphorylation process
has also been suggested. Transfection of the oncogenic rus gene en-
hances the phosphorylation and transactivating function of NF-IL6
(Nakajima et al., 1993). These results imply that the IL-6-induced
activation of gpl30-associated tyrosine kinase may lead to the activa-
tion of Ras and, subsequently, MAP kinase, resulting in the functional
activation of NF-IL6.
c. SOLUBLE FORMS OF INTERLEUKIN-6 RECEPTORCOMPONENTS
Naturally produced soluble IL-6R protein, which retains its ability
to bind IL-6, was observed first in human urine. ILS-binding protein,
whose partial amino acid sequence was identical to that of previously
cloned IL-6R, was purified by IL-6-coupled column chromatography
(Novick et al., 1989). In human and mouse serum, the presence of
natural soluble IL-6R, which is capable of binding IL-6 and mediating
signals via membrane-anchored gp130, has been demonstrated (No-
vick et d . , 1991; Honda et d . , 1992; Suzuki et d . ,submitted). This
implies a possible physiological role for serum-soluble IL-6R in modu-
lating IL-6 functions. Although the mechanism of production of solu-
ble IL-6R has not fully been elucidated, identification of mRNA encod-
ing the transmembrane domainless form, possibly created by
alternatively splicing, was reported (Lust et aZ., 1992). Autoimmune-
prone MRL/lpr mice appear to produce serum-soluble IL-6R at a
significantly high concentration, compared with normal mice. In addi-
tion, an age-associated increase in serum-soluble IL-6R levels is ob-
served in mice of this strain (Suzuki et al., submitted). In MRL/lpr
mice, the serum level of IL-6 also increases according to age (Tang et
al., 1991).Taken together, these elevations might be involved in the
pathogenesis of autoimmune symptoms in MRL/lpr mice. A soluble
forms of the IL-6 signal-transducing receptor component, gp130 is also
found in human serum. Serum-soluble gp130 is shown to negatively
regulate the IL-6 signal, suggesting its physiological role (M. Narazaki
et al., submitted).
V. Biological Function of Interleukin-6

A. GROWTH REGULATORY FUNCTIONS
IL-6 enhances, inhibits, or has no effect on cell proliferation depend-
ing on the cell type.
1 . Growth-Stirnulatory Effect
Interleukin-6 promotes growth and may be an autocrine growth
factor in a number of plasmacytomas and myelomas (Vink et al.,
1990; Kawano et al., 1988), EBV-transformed B lymphocytes (Tosato
et al., 1990; Yokoi et al., 1990), several T and B lymphomas (Shimizu
et al., 1988; Yee et al., 1989), mesangial cells (Horii et al., 1989),
vascular smooth muscle cells (Nabata et al., 1990), Kaposi sarcoma-
derived cells (Miles et al., 1990), renal carcinoma (Miki et al., 1989),
Pagetic osteoclasts (Roodman et al., 1992) and psoriatic keratinocytes
(Grossman et al., 1989).
2. Growth-lnhibitory Effect
Dose-dependent growth inhibition of IL-6 is observed in a number
of human breast carcinoma cell lines including ductal carcinomas and
adenocarcinomas (Chen et al., 1988). IL-6 also affects the cell mor-
phology and behavior of breast cancer cells: colonies lose epithelial
morphology and contain dispersed fusoid cells, with few contacts,
increased motility, loss of cytoskeletal organization, and loss of des-
mosomes (Tam et al., 1989). Although IL-6 stimulates growth of plas-
macytomas, myelomas, and several B lymphomas as described, it can
also inhibit growth of certain chronic B leukemic cells and B lympho-
mas (Chen et al., 1988). Thus, IL-6 acts as a positive and negative
regulator of B lymphocyte growth. M12 murine B lymphoma cells,
which lack the IL-6 receptor but have the gp130 transducer, became
growth inhibited by IL-6 on transfection by the IL-6 receptor gene
(Taga et al., 1989). IL-6 inhibits the growth of certain myeloid leuke-
mic cells and induces the differentiation of these cells into mature
macrophage-like cells (Shabo et al., 1988; Miyaura et al., 1988;
Lotem et al., 1989). Inhibition of acute myelogeneous leukemia
(AML) development by IL-6 treatment was observed (Givon et al.,
1992), IL-6 inhibits the proliferation of bone marrow and tissue mac-
rophages (Riedy and Stewart, 1992). IL-6 also inhibits melanocyte
proliferation (Morinage et al., 1989) and the growth of early-stage
melanoma cells (Lu et al., 1992). IL-6 has been reported to inhibit
the proliferation of endothelial cells and diploid fibroblasts under
particular experimental conditions (Kohase et al., 1986).
B. IMMUNE REGULATION
1. Effects on B Cells
Interleukin-6 was first recognized as a T cell-derived factor acting
on B cells to induce immunoglobulin (Ig) secretion. IL-6 acts mainly
on the late phase of the B cell differentiation pathway, consistent
with the finding that IL-6R is expressed on activated B cells but not
resting B cells (Taga et al., 1987). IL-6 acts on mitogen-activated B
cells to induce IgM, IgG, and IgA production without stimulating B
cell proliferation (Muraguchi et al., 1988; Beagley et al., 1989). In
this case, IL-6 shows no differential effects among IgM-, IgG-, and
IgA-committed B cells, in contrast to other interleukins, such as IL-4
and IL-5, which display preferential effects on IgE and IgA secre-
tion. Anti-IL-6 antibody completely inhibits Ig production. The es-
sential role of IL-6 is also demonstrated in polysaccharide-specific Ig
production (Ambrosino et al., 1990), IL-4-dependent IgE response
(Vercelli et al., 1989), tetanus toxoid-specific Ig production (Brieva et
al., 1990), and influenza A virus-specific primary response (Hilbert et
al., 1989). In uiuo antigen-stimulated lymphoblastoid B cells re-
sponded well to IL-6 and differentiated into antibody-producing
cells in uitro (Lue et al., 1991). IL-6 enhanced the in uiuo secondary
anti-SRBC antibody production in mice (Takatsuki et al., 1988).
These experimental results demonstrate that IL-6 functions as a B
cell differentiation factor in uitro as well as in uiuo.
Interleukin-6 is also a potent growth factor for hybridoma/
plasmacytoma/myeloma cells and only 2 pg/ml rIL-6 could induce
50% of the maximal proliferation in myeloma cell lines (Van Damme
et al., 1987b; Aarden et al., 1987; Nordan et al., 1987). This concen-
tration of IL-6 is 100-fold less than that required for Ig induction in B
cells. Therefore, IL-6-dependent B cell hybridoma lines, such as B9
and 7TD1, provide us with an extremely specific and sensitive bio-
assay for IL-6. IL-6 is found to increase the frequency of develop-
ment of hybridomas producing monoclonal antibodies and to aug-
ment cloning efficiency; therefore, IL-6 is now used to establish
hybridoma cell lines (Matsuda et al.,1988; Harris et al., 1992). IL-6
also promotes the proliferation of EBV-infected B cells and permits
their growth at low cell densities (Tosato et al., 1988).
2. Effect on T Cells
Interleukin-6 is involved in T cell activation, growth, and differen-
tiation. IL-6 stimulates the proliferation of peripheral T cells and ma-
ture thymocytes activated with lectins or anti-T cell receptor mono-
clonal antibodies (Garman et al., 1987; Lotz et al., 1988; Uyttenhove

et al., 1988).IL-6 induces not only proliferation but also differentia-
tion of cytotoxic T lymphocytes (CTLs) (Okada et al., 1988; Takai et
al., 1988, Renauld et al., 1989). Anti-IL-6 antibodies completely
block cytolytic and proliferative T cell responses, supporting the im-
portance of IL-6 in the growth and differentiation of T cells. In most
cases, the effect of IL-6 is evident in the presence of other stimuli,
including IL-1, TNF, and PHA. IL-6 and IL-1 synergize for T cell
proliferation (Houssiau et al., 1988a). IL-1 induces IL-6 production
and increases the sensitivity to IL-6 (Helle et al., 1988). The involve-
ment of IL-2 in IL-6 (or IL-1 + IL-6)-mediated T cell proliferation
and differentiation was demonstrated by the observation that T cells
stimulated with IL-6 produced IL-2 and that anti-IL-2 receptor mAb
completely inhibited IL-6 (or IL-1 + IL6)-induced murine T cell
proliferation and differentiation. These results suggests that IL-1 and
IL-6 could exert their T cell growth activity by upregulating the pro-
duction of and the response to IL-2. Part of the synergistic interaction
between IL-6 and IL-1 seems to result from the mechanism by which
IL-6 converts T cells to an IL-2-responsive state b y the transition
from Go to an early stage in GI and the induction of IL-2 receptor
(Tac antigen) expression (Noma et al., 1987; Le et al., 1988), whereas
IL-1 and IL-6 both act on IL-2 production (Garman et al., 1987;
Houssiau et al., 1988a). In primary CD4+ or CD8+ T cells, T cell
receptor (TCR) crosslinking by anti-CD3 mAb induces both IL-2 re-
ceptor expression and responsiveness to exogenous IL-2, but is not
sufficient to induce either IL-2 secretion or T cell proliferation. IL-2
secretion and proliferation require both TCR crosslinking and anti-
gen presenting cell (APC)-derived costimulatory signals. It is demon-
strated that either IL-1 or IL-6 can replace the requirement for
APC-derived costimulatory signals for IL-2 secretion and prolifera-
tion (Kasahara et al., 1990; Lorre et aZ., 1990). IL-6 also augments the
activity of human natural killer cells (Luger et al., 1989).
C. HEMATOPOIESIS
1 . Effects on Hematopoietic Progenitor Cells
Hematopoiesis is regulated by a variety of growth- and differ-
entiation-inducing factors. In the steady state, the majority of he-
matopoietic stem cells are dormant and reside in the Go phase of
the cell cycle. Ikebuchi et al. (1987) showed that IL-6 acted syner-
gistically with IL-3 in uitro to hasten the appearance of multilineage
blast cell colonies grown from murine spleen cells. A similar synergy
between IL-6 and IL-3 was shown using purified human bone
marrow progenitors. In this case, IL-6 induced a Go-to-G1 progres-
sion of hematopoietic stem cells, whereas IL-3 did not trigger their
emergence from the Go phase, but was necessary for the proliferation
of these cells. Continuous perfusion of IL-6 into normal mice in-
creased splenic CFU-s numbers (Suzuki et al., 1989). Bone marrow
transplanted mice that were subsequently treated with 1L-6 exhib-
ited both enhanced hematopoietic repopulation and enhanced sur-
vival (Okano et d., 1989). IL-6 or a combination of IL-3 and IL-6
given to mice with radiation-induced hematopoietic suppression was
shown to facilitate multilineage recovery. Rennick et al. (1989) dem-
onstrated the ability of IL-6 to interact with IL-4, G-CSF, M-CSF,
and GM-CSF to selectively enhance the clonal growth of progenitor
cells at specific stages of lineage commitment and maturation. IL-1,
IL-6, and KL had limited ability to stimulate the proliferation of mu-
rine hematopoietic progenitor cells. IL-6 and IL-3 were able to stim-
ulate an immature population of progenitor cells, and IL-6 was
shown to increase the number of high-proliferative-potential colony-
forming cells (HPP-CFC) stimulated by IL-3, IL-4, G-CSF, M-CSF,
and GM-CSF from d4 5-FU BM cells. When used alone, IL-6 was
shown to directly support the in uitro proliferation of murine GM
progenitors, as well as to directly promote megakaryocyte maturation
in uitro. Much smaller amounts of IL-6 induced a neutrophilia, a
slight lymphopenia, and a reticulocytosis (Ulich et al., 1989).
Interleukin-6 may be useful in the application of retroviral gene
transfer methods to human cells. Retroviral-directed gene integration
requires active cell cycle and reconstitution requires maintenance of
self-renewal capacity in the donor cell population. The combination
of IL-3 and IL-6 or Steel factor and IL-6 has been shown to improve
the efficiency of retroviral-mediated gene transfer into reconstitut-
ing hematopoietic stem cells (Bodine et al., 1989; Dick et al., 1991;
Apperley et al., 1991; Luskey et al., 1992).
2. Effects on Megakaryocytes
Human megakaryocytopoiesis is a complex phenomenon that in-
cludes proliferation of committed megakaryocytic progenitor cells,
and cellular maturation comprising nuclear polyploidization, growth
in size, and generation of cytoplasmic lineage markers. IL-3, GM-
CSF, erythropoietin, and Steel factor are able to induce proliferation
and differentiation of the committed progenitors, but none of these
factors has been shown to be specific for the megakaryocyte lineage.
In contrast, late stages, including polyploidization and maturation,
were under the control of a specific factor(s) called thrombopoietin.

IL-6 has been found to function as thrombopoietin (Ishibashi et al.,
1989a,b; Asano et al., 1990; Hill et aZ., 1990). IL-6 induces not only
the in uitro maturation of megakaryocytes (increase in ploidization,
size, and acetylcholine esterase activity) but also in in uiuo increase
in platelet counts in mice and monkeys. Transgenic mice carrying
human IL-6 are shown to have an increased number of megakary-
ocytes in their marrow (Suematsu et al., 1989). IL-6 and IL-6R are
constitutively expressed by human megakaryocytes, suggesting that
normal human megakaryocytopoiesis might be regulated in part by
an autocrine loop (Navarro et al., 1991). Whether or not IL-6 is the
physiological regulator of thrombopoiesis is, however, controversial
(Hill et al., 1992b; Straneva et al., 1992). Reactive or secondary
thrombocytosis is observed in various conditions such as inflam-
mation, following surgery, or in trauma and malignancy, accom-
panied by increased levels of serum IL-6. On the other hand, no
elevation of serum IL-6 levels has been observed in patients with
myeloproliferative disorders and idiopathic thrombocytopenic pur-
pura. Administration of anti-IL-6 antibody does not cause thrombocy-
topenia in uiuo. Furthermore, decreased numbers of circulating
platelets are not associated with increased levels of serum IL-6, al-
though increased IL-6 levels are more closely related with the exis-
tence of ongoing inflammatory processes. Therefore, IL-6 may not be
required for steady-state thrombopoiesis, but may play a role in situa-
tions of hematopoietic stress. In any case, the effects of IL-6 on
thrombocytes are of potential clinical importance for the treatment of
thrombocytopenia.
3. Effects on Macrophage Differentiation
Human and mouse myeloid leukemic cell lines can be induced to
differentiate into macrophages in uitro by several factors including
G-CSF, macrophage-granulocyte-inducing factor 2 (MGI-2), and
leukemia-inhibitory factor (LIF). IL-6 was shown to be identical to
MGI-2, which could induce the differentiation of a murine myeloid
leukemia cell line, M 1 (Shabo et d.,1988; Miyaura et al., 1988; Chiu
et al., 1989; Lotem et al., 1989). IL-6 inhibits the growth of human
U937 and murine M 1 myeloid leukemic cell lines, and induces the
differentiation of these cells into mature macrophage-like cells. At
the same time, IL-6 enhances phagocytosis and expression of a num-
ber of macrophage differentiation antigens including Mac-1 and
Mac-3 and yFc receptors, major histocompatibility complex class I,
nonspecific esterases, lysozyme, 2',5'-A-synthetase, c-fms (M-CSF re-
ceptor), indicating the functional differentiation into mature macro-

phages. In human myeloid cell line U937, IL-6 has some effects
alone, which can be enhanced by association with other cytokines
such as IFN-y, IL-1, LIF, G-CSF, and GM-CSF. HL-60 cell growth is
reduced by IL-6 with GM-CSF and differentiation is seen with TNF
and IFN-y. Shabo et al. (1989) proposed the hypothesis that IL-6 and
GM-CSF are autocrine differentiating factors which are synthesized
in myeloid cells as a second messenger of other growth factors, based
on the fact that all CSFs including IL-3 can induce the production of
IL-6 and GM-CSF in normal myeloid precursors.
D. ACUTE-PHASE PROTEIN SYNTHESIS IN HEPATOCYTES
Inflammation is accompanied by the acute-phase response which is

characterized by significant alterations in the serum levels of several
plasma proteins, known as acute-phase proteins (APPs) (Kushner,
1982; Koj, 1985). APP production is reflected in the increase in eryth-
rocyte sedimentation rate, which is used as a cursory indicator of
inflammation in humans. The acute-phase response is well preserved
throughout phylogeny and is considered to serve host defense sys-
tems by protecting the generalized tissue destruction associated with
inflammation. In fact, many APPs are antiproteinases, opsonins, or
blood-clotting and wound-healing factors.
Acute-phase proteins are synthesized mainly by the liver. Both an
increase and a decrease in synthesis of APPs are seen in the acute-
phase response. Concentrations of several plasma proteins increase
dramatically. For example, more than 1000-fold increased levels of
both C-reactive protein (CRP) and serum amyloid A (SAA) are ob-
served in sera of severely infected individuals. Other plasma proteins
increase moderately (e.g., fibrinogen, a1AT, complement proteins
factor B and C3). In contrast, there is a decrease in several plasma
proteins such as albumin, transferrin, cyz-globulin, and transthyretin.
The biosynthesis of acute-phase proteins by hepatocytes is regu-
lated by the hepatocyte-stimulating factor (HSF). It has been shown
that HSF is indentical to IL-6 (Gauldie et al., 1987; Andus et al.,
1987). rIL-6 induced synthesis and secretion of a wide spectrum of
acute-phase proteins from primary hepatocytes and hepatocyte cell
lines, including SAA, CRP, haptoglobin, al-antitrypsin, al-acid glyco-
protein, and al-antichymotrypsin, whereas albumin and transferrin
were decreased. Induction of CRP, SAA, and fibrinogen by condi-
tioned medium was completely inhibited by antibodies to rIL-6.
In vivo administration of IL-6 in rats induced a typical acute-
phase reaction similar to that induced by turpentine (Geiger et al.,
1988). An IL-6-mediated increase in serum acute-phase proteins was

demonstrated in the monkey (Asano et al., 1990). It was also reported
that serum levels of IL-6 correlated well with those of CRP and fever
in patients with severe burns (Nijsten et al., 1987), and an increase in
serum IL-6 was observed before an increase in serum CRP in pa-
tients undergoing surgery (Nishimoto et d., 1989; Shenkin et d.,
1989). The results confirmed the in uiuo effect of IL-6 in the acute-
phase reaction.
Besides IL-6, several cytokines have been found capable of di-
rectly inducing acute-phase proteins from the liver: IL-1, TNF-a,
IL-11, LIF, TGF-P, and oncostatin M. IL-1/TNF and IL-6 act on
some genes (e.g., al-acid glycoprotein) in a synergistic manner and
on other genes (e.g., fibrinogen) in an additive or negative manner.
LIF was discovered because of its ability to induce terminal differen-
tiation of M 1 myeloid leukemia cells (Gearing et al., 1987) and in-
hibit differentiation of embryonic stem cells (Williams et al., 1988),
and is now found to be a multifunctional cytokine like IL-6. Onco-
statin M is a cytokine expressed in activated human T lymphocytes
and monocytes, orginally identified as a growth regulator for certain
tumor cell lines (Zarling et al., 1986). LIF and oncostatin M regu-
late the same set of genes as does IL-6 (Baumann and Wong, 1989;
Richard et al., 1992). In this regard, it is noteworthy that the high-
affinity receptors for LIF and oncostatin M share gp130, a signal
transducer of IL-6 (Gearing et al., 1992). IL-11, the recently discov-
ered factor (Paul et al., 1990), is shown to exert IL-6-like effects on
liver cells (Baumann and Schendel, 1992). TGF-P can affect hepatic
synthesis and secretion of a subset of acute-phase proteins, both di-
rectly and by modulating the effect of IL-6 (Mackiewicz et al., 1990;
Morrone et al., 1989). The affected group of plasma proteins is dis-
tinct from those affected by IL-6.
It has been shown that glucocorticoids potentiate the effect of cy-
tokines on induction of some, but not all, human acute-phase
proteins, although they have no stimulatory action on their own.
Aside from its role as an inducer of acute-phase proteins, IL-6 acts on
the central nervous system to induce fever and to elicit the release
of adrenocorticotropic hormone (ACTH) (LeMay et al., 1990; Naitoh
et al., 1988).ACTH in turn increases the synthesis of glucocorticoids
in adrenal glands. Elevated levels of circulating glucocorticoids syn-
ergize in IL-6 in inducing the increased hepatic synthesis and se-
cretion of acute-phase proteins. Glucocorticoids also upregulate
high-affinity IL-6 receptors and gp130 on hepatocytes and thereby
augment the synergy between glucocorticoids and IL-6 in the
INTERLEUKIN-6 IN BIOLOGY A N D MEDICINE 27
synthesis of acute-phase proteins by hepatocytes (Snyers et al., 1990;

Schooltinck et al., 1992). On the other hand, glucocorticoids decrease
the monocytes/macrophages to produce IL-6, IL-1, and TNF-a
feedback mechanism preventing excessive production of inflamma-
tory cytokines. These findings show an important regulatory interac-
tion between the immune and neuroendocrine systems.
E. A PROINFLAMMATORY
AS WELLAS AN
ANTI-INFLAMMATORY CYTOKINE
Interleukin-1 and T N F are known as potent inducers of proteinase
production by fibroblasts, synoviocytes, and chondrocytes, and are
recognized as the principal mediators of inflammatory connective tis-
sue destruction. IL-1 and T N F activate the endothelial cells to stimu-
late the synthesis of intercellular adhesion molecule 1 (ICAM-1) and
to induce the expression of endothelial-leukocyte adhesion molecule
1 (ELAM-l), causing neutrophils, monocytes, and lymphocytes to ad-
here. In contrast to IL-1 and TNF, IL-6 does not induce adhesion
molecules by endothelial cells. IL-6 does not stimulate the produc-
tion of collagenase, matrix metalloproteinase, or stromelysin. Rather,
IL-6 is identified as a potent inducer of a tissue inhibitor of metallo-
proteinase l/erythroid potentiating activity (TIMP/EPA) (Sato et al.,
1990; Lotz and Guerne, 1991). The acute-phase proteins regulated
primarily by IL-6 are antiproteinases, oxygen scavengers, and clot-
ting factors, although the true physiologic role of the acute-phase
proteins remains unclear. Although IL-1 and T NF have extremely
high toxicity in uiuo, IL-6 is tolerable at a high concentration in sera.
IL-6 does not cause shock in mice (Neta et al., 1988), dog (Preiser et
al., 1991) or primates (Asano et al., 1990) regardless of the
amount given either alone or with TNF, although there are re-
ports that antibodies to IL-6 reduced LPS-caused mortality in mice
(Starnes et al., 1990; Heremans et al., 1992). Furthermore, IL-6 in-
hibited significantly the acute neutrophilic exodus and T N F produc-
tion caused by an intratracheal injection of LPS, providing evidence
that IL-6 may represent an endogenous negative feedback mecha-
nism to inhibit endotoxin-initiated cytokine-mediated acute inflam-
mation (Ulich et al., 1991). It has, however, been shown that IL-6 is
the major inducer of phospholipase A2 (PLA2) gene expression in
human hepatoma cells (Crow1 et al., 1991). PLA2 is an enzyme that
plays an important role in inflammation by producing potent lipid
mediators, such as leukotrienes, prostaglandins, and platelet-
activating factor. Serum levels of PLA2 activity are elevated in septic
shock and rheumatoid arthritis. Furthermore, IL-6 potentiated IL-1-
and TNF-stimulated collagenase and PGE2 production by chondro-

cytes, although IL-6 by itself had no capacity to induce either col-
lagenase or PGEz production by nasal chondrocytes (Smith et al.,
1992). It is feasible to assume that inflamed synovium-derived IL-6,
IL-1, and TNF-a might interact to augment proteinases and pros-
tanoid production by chondrocytes in certain pathological conditions.
Thus, IL-6 has two aspects as a proinflammatory as well as an anti-
inflammatory factor.
F. EFFECTON BONEMETABOLISM
Interleukin-6 is an important regulator of bone remodeling. In nor-
mal young adults, there is a balance between the processes of bone
formation by osteoblasts and bone resorption by osteoclasts. Such
bone remodeling is regulated by local factors referred to as osteotro-
pic cytokines that are generated in the microenvironment of the
remodeling unit. The osteotropic cytokines include IL- 1, TNF,
CSFs, and IL-6. IL-6 is produced locally in bone by osteoblasts un-
der the direction of parathyroid hormone or other cytokines such as
IL-1 and TNF (Lowik et al., 1989; Ishimi et al., 1990; Feyen et al.,
1989). Osteoclasts also produce IL-6 as do a variety of other cells in
the marrow microenvironment. IL-6 stimulates early osteoclast pre-
cursor formation from cells present in GFU-GM colonies (Kurihara et
al., 1990). Moreover, IL-6 stimulates the recuitment as well as the
formation of osteoclasts and the release of 45Ca from prelabeled fetal
mouse bone, and induces bone resorption cooperatively with IL-1 in
vitro. Also, nude mice inoculated with Chinese hamster ovary cells
transfected with the human IL-6 gene exhibited a significant increase
in blood calcium which was associated with increased levels of se-
rum IL-6, demonstrating that IL-6 stimulates bone resorption (Black
et al., 1991). Evidence for the direct role of IL-6 in osteoclastogenesis
in vivo has been demonstrated. IL-6 production by bone and marrow
stromal cells is suppressed by 17P-estradiol in oitro (Girasole et al.,
1992). In mice, ovariectomy (estrogen loss) enhanced osteoclast de-
velopment. The enhanced osteoclast formation was prevented by ad-
ministration of anti-IL-6 antibody in d u o , suggesting that estrogen
loss upregulates osteoclastogenesis through an increase in the produc-
tion of IL-6 in the microenvironment of the marrow (Jilka et al.,
1992).
G. EFFECTON SKIN
Skin is one of the major sites of IL-6 production. Keratinocyte cell
lines can be induced to express high levels of IL-6 mRNA and
protein by a number of agents including LPS, phorbol esters, various
INTERLEUKINS IN BIOLOGY A N D MEDICINE 29
toxins, and cytokines such as IL-1 and TNF. IL-6 stimulates prolifer-
ation of normal human keratinocytes (Grossman et al., 1989; Yoshi-
zaki et al., 1990). In contrast to other cell types including fibroblasts
and macrophages, IL-4 induces IL-6 in the keratinocytes. Physico-
chemical agents such as thermal injury and ultraviolet irradiation
lead to increased production of IL-6 by the skin (Kirnbauer et al.,
1991). Increased systemic levels of IL-6 can be detected in human
volunteers and in experimental animals following ultraviolet irradi-
ation (Urbanski et al., 1990). Acute exposure to ultraviolet light
causes cutaneous inflammation, malaise, somnolence, chills, and fe-
ver. Plasma IL-6 levels correlate remarkably with the course of fever
followed by an increase in acute-phase proteins such as CRP. IL-6,
which is released by keratinocytes following ultraviolet exposure,
may gain access to the circulation and may function as an important
mediator of systemic sunburn reaction.
H. EFFECTON BLOODVESSELS
The vascular endothelial cells that form the inner lining of blood
vessels play an active role in mediating an inflammatory response.
IL-1, LPS, and oncostatin M induce IL-6 production in endothelial
cells (Sironi et al., 1989; Jirik et al., 1989; Brown et al., 1990). IL-6
caused a significant increase in the mRNA level of platelet-derived
growth factor (PDGF) in cultured human endothelial cells (Calderon
et ul., 1992). PDGF stimulates the proliferation and migration of vas-
cular smooth muscle cells (VSMCs) and fibroblasts. PDGF is also
chemotactic for monocytes and neutrophils and induces them to re-
lease inflammatory mediators such as superoxide anion and lysozy-
ma1 enzymes. IL-6 is also shown to increase the permeability of en-
dothelial cells (Maruo et d., 1992). These series of events are
considered to contribute to vasculitis and atherosclerogenesis.
VSMCs also express IL-6 in response to IL-1 (Loppnow and Libby,
1990). IL-6 stimulates the proliferation of VSMCs in a PDGF-
dependent manner (Nabata et al., 1990; Ikeda et al., 1991). There-
fore, IL-6 is released by VSMCs and promotes the growth of VSMCs
in an autocrine manner via induction of endogenous PDGF pro-
duction.
Endothelial cells continuously form nitric oxide from L-arginine.
This basal release of nitric oxide by the endothelium accounts for the
biological properties of the so-called endothelium-derived relaxing
factor (EDRF) and is involved in the regulation of regional vascular
resting tone of different vascular beds, including the proximal and
resistance coronary vessels. It has been demonstrated that IL-6 in-
hibits heart contractility in a concentration-dependent, reversible
30 SHIZUO AKlRA ET AL.
manner (Finkel et al., 1992). The nitric oxide synthase inhibitor N G -

monomethy-L-arginine (L-NMMA) blocked the negative inotropic ef-
fect, whereas L-arginine reversed the inhibition by L-NMMA, sug-
gesting that the direct negative inotropic effect of IL-6 is mediated
through a myocardial nitric acid synthase.
Serum IL-6 levels are reported to become elevated in patients of
myocardial infarction (Entman et al., 1991; Ikeda et al., 1992b). The
effects of L-NMMA on coronary blood flow and resistance are shown
to be attenuated substantially in postinfarction reactive cardiac hy-
pertrophy (Drexler et al., 1992). Septic shock is characterized by car-
diocirculatory insufficiency in which vascular hyporesponsiveness is
a major determinant of mortality. Correlations between nitric oxide
production and hypotension in shock have been observed (Fleming
et al., 1990; Westenberger et al., 1990). Therefore, in both myocardial
postinfarction and septic shock, monokines including IL-6 may de-
press the contractile function by activating the L-argininehitric oxide
pathway of the vascular smooth muscles.
I. EFFECTON NEURONALCELLS
Interleukin-6 is produced in neuronal cells by specific stimuli, and
it also exerts some effects on them. LPS, IL-1, and y-interferon
(IFN-y) induce expression of mRNA for IL-6 in cultured astroglial
cells and microglia. Either IL-lP or TNF exerts a strong inducing
signal for IL-6 in primary rat astrocytes (Lieberman et al., 1989).
Virus-infected microglial cells and astrocytes produce IL-6 (Frei et
al., 1988). IL-6 stimulates astrocytes and some other neural cells to
proliferate. IL-6 was found to induce the differentiation of PC12 cells
into neural cells (Satoh et al., 1988). Human IL-6 can support the
survival of the cultured cholinergic neurons in addition to regulating
dopamine synthesis (Hama et al., 1989).
Noteworthy is the presence of bidirectional communication be-
tween the immune and neuroendocrine systems. The neuroendo-
crine system, particularly the hypothalamic-pituitary-adrenal (HPA)
axis, can modulate immune responses, whereas inflammatory cy-
tokines can modulate neuroendocrine activities. Centrally adminis-
tered IL-6 rapidly exerts a stimulatory effect on ACTH release in
conscious male rats (Naitoh et al., 1988). IL-6 also stimulates the re-
lease of a variety of anterior pituitary hormones, such as prolactin,
growth hormone, and luteinizing hormone (Spangelo et al., 1989).
IL-1 injected into the lateral brain ventricle of rats increases circu-
lating IL-6 levels in hypophysectomized and adrenalectomized rats
(De Simoni et al., 1990). Corticotropin-releasing factor (CRF) is
shown to work as an autocrine or paracrine inflammatory cytokine.

IL-1 and IL-6 can induce the synthesis and secretion of CRF by hy-
pothalamic cells (Lyson et al., 1991; Navarra et al., 1990);conversely,
this neuropeptide can induce the synthesis and secretion of IL-1 and
IL-6 (Leu and Singh, 1992). Anterior pituitary cells by themselves are
found to produce IL-6 (Spangelo and MacLeod, 1990). IL-6 is pro-
duced by anterior pituitary cells in response to LPS and phorbol es-
ter and agents that elevate intracellular CAMP concentrations in ui-
tro. Also, IL-6 production by anterior pituitary cells is stimulated by
vasoactive intestinal peptide (VIP), which stimulates adenylate cy-
clase activity, causing a concentration-dependent enhancement of
IL-6 production (Spangelo and MacLeod, 1990).
In addition to increasing ACTH and CRF release from the hypo-
thalamus and pituitary, endotoxin and IL-1 also cause the adrenal to
release IL-6 directly (Judd et al., 1990). Induction of IL-6 production
by IL-1 may be potentiated markedly by the stress-induced elevation
of ACTH levels, because the effects of ACTH and IL-1 together on
IL-6 production are greater than the sum of their effects separately.
IL-6 in turn may stimulate the release of glucocorticoid from the
adrenal cortex. IL-6 not only stimulates basal corticosterone release,
but potentiates ACTH-stimulated corticosterone release (Salas et al.,
1990). Therefore, under chronic stress, IL-6 produced in the adrenal
gland may amplify the response of the adrenal cortex to ACTH.
DEVELOPMENT
J. ROLE DURING EMBRYONIC
The potential role of cytokines during embryonic development and
particularly their possible function in the development of plurip-
otent hemopoietic stem cells have been studied by several investiga-
tors. Murray et al. (1990) detected mRNA transcripts for IL-6 and LIF
but not for GM-CSF or IL-3 in mouse blastocysts at 3.5 days of gesta-
tion, suggesting that IL-6 and LIF may regulate the growth and de-
velopment of trophoblasts or embryonic stem cells. Schmitt et al.
(1991) and Burkert et al. (1991) independently detected transcrip-
tional activation of several cytokines and the corresponding receptor
genes (Epo, CSF-1, IL-4, and IL-6) during embryonic stem cell de-
velopment; however, IL-3 and GM-CSF were not expressed during
the first 24 days of embryonic stem cell differentiation, strongly sug-
gesting that IL-3 and GM-CSF are not critical to early hematopoiesis.
Rothstein et al. (1992) investigated expression of cytokines in
cDNA libraries from unfertilized eggs and two-cell, eight-cell, and
blastocyst-stage mouse embryos, and identified IL-6 transcripts as
early as the eight-cell stage, persisting into the blastocyst stage;
however, the role of IL-6 in embryogenesis awaits further experi-

mentations.
K. ROLE DURING PLACENTAL/FETAL DEVELOPMENT
Interleukin-6 has been speculated to influence placental/fetal de-
velopment. The ovarian steroids estrogen and progesterone regulate
cellular and molecular changes that occur in the uterus during the
estrous cycle. During the estrous cycle, uterine cells undergo cycles
of proliferation, differentiation, and death. Freshly explanted human
endometrial cells secrete IL-6 (Semer et aZ., 1991). Angiogenesis ac-
companies the cyclic destruction and reconstitution of the endome-
trium. IL-6 mRNA is transiently expressed during the angiogenesis
that accompanies folliculogenesis and formation of the maternal deci-
dua during early postimplantation development (Motro et al., 1990).
Uterine stromal and endothelial cells secrete IL-6, and its production
by these cells is inhibited by estrogen and/or progesterone. Activated
leukocyte products including IL-6 arrest embryonic development at
the two-cell to morula stage (Hill et al., 1987). Furthermore, IL-6
added to blastocysts on laminin-coated tissue culture wells results in
a transient inhibition of the rate of blastocyst attachment and, to a
greater extent, an inhibition of the rate of embryo outgrowth (Jacobs
et aZ., 1992). These data indicate that IL-6 can have inhibitory effects
on preimplantation embryos.
Interleukin-6 is produced by extraembryonic tissues later in gesta-
tion and may act on maternal tissue to control interactions between
the fetus and the mother, such as angiogenesis, the formation of new
blood vessels. This important process accompanying the develop-
ment of the placenta and the uterus following inplantation of the
embryo may be under fetal as well as maternal control. Studies with
human placental trophoblasts or whole placental tissue, which is ex-
traembryonic but primarily fetal in origin, have demonstrated the
presence of both IL-6 mRNA and biologically active protein (Kameda
et aZ., 1990; Duc-Goiran et aZ., 1989). IL-6 produced by human tro-
phoblasts could act on trophoblasts to stimulate the release of human
chorionic gonadotropin through a pathway distinct from the one in-
volving gonadotropin-releasing hormone (Nishino et al., 1989). As
hCG in turn stimulates the placenta to produce progesterone, which
then acts on uterine tissue to maintain an abundant supply of blood
vessels, placental-derived IL-6 may be important in the initiation of
this angiogenic process.
Biological functions of IL-6 are summarized in Table 111.
TABLE 111
BIOLOGICAL
FUNCTIONSO F INTERLEUKIN-6
Effect on €3 cells Immunoglobulin production

Proliferation of hybridoma/plasmacytoma/myeloma
cells
Proliferation of EBV-infected B cells
Effect on T cells Proliferation and differentiation of T cells
Differentiation of cytotoxic T lymphocytes
Induction of IL-2 receptor (Tac antigen) expression and
IL-2 production
Augmentation of natural killer activities
Effect on hematopoietic Enhancement of multipotential hematopoietic colony
progenitor cells formation
Effect on megakaryocytes Megakaryocyte maturation
Effect on macrophages Growth inhibition of myeloid leukemic cell lines
Macrophage differentiation of myeloid leukemic cell
lines
Effect on hepatocytes Acute-phase protein synthesis
Effect on bone metabolism Stimulation of osteoclast formation
Induction of bone resorption
Effect on blood vessels Induction of platelet-derived growth factor
Proliferation of vascular smooth muscle cells
Negative inotropic effect on heart
Effect on neuronal cells Neural differentiation of Pc12 cells
Support of survival of cholinergic neurons
Induction of adrenocorticotropic hormone synthesis
Effect on placenta Secretion of human chorionic gonadotropin by
trophoblasts
VI. Interleukin-6 and Disease

A. B CELLNEOPLASIA
Multiple myeloma is a human B cell neoplasm characterized by
accumulation, in the bone marrow, of plasma cells that secrete mono-
clonal immunoglobulins and by multiple osteolytic lesions. IL-6 is
important for in vivo growth of murine plasmacytomas and human
myelomas (Van Damme et a[., 1987b; Kawano et al., 1988), sug-
gesting a possible involvement of IL-6 in the generation of plasma-
cytomas/myelomas. There is a significant association between the oc-
currence of plasma cell neoplasias and chronic inflammation (Isobe
and Osserman, 1971; Isomaki et al., 1978). Plasmacytomas can be
induced in BALB/c mice by mineral oils such as pristane that are
potent inducers of chronic inflammation and IL-6 production (Potter
and Boyce, 1962). Indomethacin inhibits plasmacytogenesis (Potter

et al., 1985) and inhibits the elevation of IL-6 in pristane-treated
mice (Shacter et al., 1992).
Kawano et al. (1988) reported that IL-6 is a possible autocrine
growth factor for human myeloma cells, including human myeloma
cell line U266, on the basis of three pieces of evidence: (1) IL-6
induced in uitro growth of myleoma cells freshly isolated from pa-
tients with multiple myeloma. (2) Myeloma cells spontaneously pro-
duced IL-6 and expressed the IL-6 receptor. (3) In uitro growth of
myeloma cells was specifically inhibited by anti-IL-6 antibody. In
support of the existence of IL-6-mediated autocrine growth, Schwab
et al. (1991) have shown that the addition of a neutralizing anti-IL-6
monoclonal antibody or IL-6 antisense oligonucleotides can inhibit
proliferation of the human myeloma cell line U266, and these effects
are reversed by adding IL-6. A similar finding is presented by Levy
et al. (1991). It have also been demonstrated that IL-1 or IFN-a stim-
ulated the growth of human myeloma cells by inducing autocrine
production of IL-6 in myeloma cells (Kawano et al., 1989; Jourdan et
al., 1991); however, Klein et al. (1989) were unable to confirm the
autocrine hypothesis in human myelomas and proposed a paracrine
hypothesis instead. They demonstrated significant IL-6 mRNA ex-
pression in bone marrow stromal cells, not purified myelomas cells,
from most of the myeloma patients in uiuo (13119 patients). Bone
marrow stromal cells from multiple myelomas actively produce IL-6,
although normal bone marrow stromal cells do not (Nemunaitis et al.,
1989). Activated multiple myeloma stromal cells may play a role in
supporting the growth and final differentiation of malignant B cells of
peripheral origin and further promoting the recruitment of circu-
lating osteoclast precursors and the growth of osterclasts, resulting in
bone destruction (Caligaris-Cappio et al., 1991). Indeed, a significant
increase in bone resorption is observed from the early stage of multi-
ple myeloma. Together, these pieces of evidence indicate that IL-6
functions as an autocrine as well as paracrine factor in myeloma cells.
Serum levels of IL-6 reflect disease severity in plasma cell dyscra-
sias. In the sera of patients with advanced multiple myeloma in-
creased levels of IL-6 have been described, whereas in early stages
IL-6 is usually not elevated (Bataille et al., 1989). It is possible that,
in some tumors, high serum levels of IL-6 might reflect a progression
from paracrine to autocrine growth in myeloma cells (Jernberg-
Wiklund et al., 1992).
Activation of the IL-6 and the IL-6R genes through viral insertion
has been reported. A murine plasmacytoma cell line, MPC11, consti-
INTERLEUKINS IN BIOLOGY AND MEDICINE 35
tutively produced IL-6 owing to the insertion of an intracisternal A

particle (IAP) retrotransposon 18 bp 5’ of the transcriptional start site
of the IL-6 gene (Blankenstein et al., 1990). The IL-6 gene but not
the IL-6 receptor gene is occasionally rearranged in patients with
mutiple myelomas (Fiedler et al., 1990). Enhanced expression of the
IL-6 receptor was observed in a murine plasmacytoma cell line,
P3U1, in which the intracytoplasmic region of the IL-6R was
replaced with part of the long terminal repeat (LTR) of the IAP gene
(Sugita et al., 1990). Transfection with an IL-6 cDNA was recently
shown to increase the tumorigenicity of an IL-6-dependent B cell
hybridoma and a mouse plasmacytoma (Tohyama et al., 1990; Vink et
al., 1990). The increase in tumorigenicity was inhibited in the
animals treated with monoclonal antibodies capable of blocking the
binding of IL-6 to its receptor.
A similar autocrine growth mechanism is also suggested in EBV-
transformed B cells. EBV is a herpesvirus that preferentially infects
B lymphocytes and induces proliferation, Ig secretion, and immor-
talization. EBV infection appears to play a pathogenetic role in the
development of endemic Burkitt lymphoma and in the recently
identified AIDS-associated Burkitt lymphoma. The continuous pro-
liferation of EBV-infected B cells appears to depend on autocrine
secretion of cytokines, including IL-1 and IL-6 (Scala et al., 1985;
Tosato et al., 1990; Yokoi et al., 1990). The constitutive expression of
the exogenously introduced IL-6 gene in EBV-infected B cells led to
an altered pattern of growth and to a malignant phenotype, as shown by
clonogenicity in soft agar cultures and turmorigenicity in nude mice
(Scala et al., 1990). These data suggest that the combined action of
EBV, which exerts an immortalizing function, and IL-6, which has
growth-promoting activity, can give rise to fully transformed B cell
tumors in immunodeficient subjects. A possible autocrine role for IL-6
has also been reported in non-Hodgkin’s lymphomas, chronic lympho-
cytic leukemias, and acute myeloid leukemias (Freeman et al., 1989;
Yee et al., 1989; Biondi et al., 1989; Oster et al., 1989).
An increased incidence of lymphoproliferative disorders [post-
transplant lymphoproliferative disorders (PTLD)] is reported in car-
diac transplant recipients receiving OKT3 monoclonal antibody
(Swinnen et al., 1990). An extremely high incidence of EBV-
associated PTLD (38%) is observed in those patients having received
multiple courses of OKT3. Before exerting its potent immune sup-
pressive properties, the OKT3 monoclonal antibody induces the acti-
vation of T cells and monocytes (Abramowicz et al., 1989; Chatenoud
et al., 1989). The observation that OKT4 monoclonal antibody and
cyclosporin A enhanced transcription of the IL-6 gene suggests that

IL-6 may play a role in the development of B cell lymphomas in
transplant recipients (Bloemena et al., 1990; Walz et al., 1990; Gold-
man et al., 1992).
B. BACTERIALAND PARASITE INFECTION
A marked increase of IL-6 levels is observed in the cerebrospinal
fluid of patients with acute bacterial infection of the central nervous
system and in the serum of patients with severe burns or sepsis (Hack
et al., 1989; Waage et al., 1989; Helfgott et al., 1989). Healthy individ-
uals have undetectable or very low concentrations of IL-6 in their sera
(always <50 pg/ml; in most cases, <lo pg/ml), whereas IL-6 plasma
levels during a bacterial infection can be increased in the range 5 to
100 ng/ml (Bauer and Herrmann, 1991). The IL-6 concentration in
these patients is correlated with the severity of illness and/or mortal-
ity rate. IL-6 levels in localized infected compartments such as
cerebrospinal fluid, synovial fluid, and amniotic fluid can be greater
than 500 ng/ml. In patients with both meningitis and bacteremia, the
concentration of IL-6 in the cerebrospinal fluid can be 10- to 100-fold
higher than that in serum.
Serum levels of IL-6 have been reported to be elevated both in mice
infected with the malaria parasite Plasmodium berghei and in patients
with Plasmodium falcipamm malaria (Kern et al., 1989).In adults with
malaria, prolonged increases in TNF and IL-6 are associated with
organ damage. The time course of raised plasma cytokine concentra-
tions may be as important to the outlook as the initial values. Sustained
increases in plasma TNF and IL-6 concentrations are predictive of a
fatal outcome (Molyneux et al., 1991).
There are several reports about the effects of IL-6 on bacterial and
parasite infections. Flesch and Kaufmann (1990)have shown that rIL-6
inhibits growth of Mycobacterium tuberculosis, whereas Denis and
Gregg (1990)and Shiratsuchi et al. (1991)reported that rIL-6 enhances
Mycobacterium auium growth in human macrophages. Tuberculosta-
tic and listericidal macrophage functions are activated by IL-6 (Kauf-
mann and Flesch, 1990).CRP is known to act as an opsonin, which may
aid the clearance of a pathogen. In fact, rats with increased serum
levels of CRP were protected from infection with Plasmodium yoelii
and protection could be abolished with an anti-CRP antiserum. This
result indicates that IL-6 may participate in protection from malaria
infection via induction of CRP. IL-6 induces an inhibitory effect at the
hepatic stage on malaria induced by P. yoelii sporozoites (Pied et al.,
1991; Nussler et al., 1991)and inhibits the development of liver schiz-
onts of P. berghei (Vreden et al., 1992). IL-6 is also shown to directly

induce the cytotoxicity of platelets toward Schistosoma mansoni (Pan-
cre et al., 1990).
C. VIRALINFECTION
Various virus infections have been shown to effectively induce the
production of IL-6 (Van Damme et al., 1989; Sehgal et al., 1988; Becker
et nl., 1991; Devergne et al., 1991). Numerous observations indicate
that the levels of IL-6 in body fluids increase rapidly after viral infec-
tion. IL-6 in cerebrospinal fluid of HTLV-1-associated myelopathy was
increased (Ohbo et al., 1991; Nishimoto et al., 1992). By infection with
experimental lymphocytic choriomeningitis virus in mice, IL-6 levels
were also approximately 60 times higher in CSF than in serum (Frei et
al., 1988). The patients positive for IL-6 generally had more severe
clinical symptoms and signs than those negative for IL-6. Regarding
the interaction between viral infection and IL-6, one of the most exten-
sively studied viruses is human immunodeficiency virus (HIV), which
is discussed in the next section.
It has been demonstrated that hepatitis B virus (HBV) uses IL-6 as a
target for attachment to cells. HBV, a member of the family of hepad-
naviridae, is a major human pathogen implicated in primary hepatocar-
cinoma. HBV receptors were detected on human liver and hepatoma
cells, on B lymphocytes, on monocytes activated by LPS, and on T cell
lines activated by Con A. It was also shown that IL-6 carries a binding
site for HBV and mediates HBV-cell interactions. Therefore, HBV
belongs to an apparently expanding family of viral pathogens using
interactions between virally encoded proteins and cytokines or cy-
tokine receptors as steps in replication (Neurath et al., 1992).
D. ACQUIREDIMMUNODEFICIENCY SYNDROME
1. Human Immunodeficiency Virus Infection
Accumulating data have indicated that IL-6 has a role in the clinical
manifestations associated with HIV infection. Initial infection with
HIV is usually followed by a long asymptomatic period characterized
by viral latency or low-level virus replication. This latency persists
until the appropriate activation signals stimulate viral transcription.
IL-6 participates in an autocrine loop which amplifies HIV-1 replica-
tion and expression. IL-6 has been shown to be involved in the activa-
tion of HIV expression in infected monocytic cells alone and in
synergy with TNF (Poli et al., 1990a). On the other hand, in vitro
infection of normal monocytes/macrophages with HIV has been found
to induce gene expression and secretion of IL-6 (Nakajima et al., 1989).
Increased levels of IL-6 have been reported in the serum of HIV-

infected patients (Breen et al., 1990; Birx et al., 1990; Honda et al.,
1990).
In addition to progressive T cell function failure, functional abnor-
malities of B cells are recognized in patients with AIDS; hypergamma-
globulinemia, an increase in Ig-secreting cells, in uiuo expression of
activation marker on circulating B cells, and presence of autoantibod-
ies in serum (Lane et al., 1983; Martinez-Maza et al., 1987). Spon-
taneous in uitro Ig production by PBMCs from HIV-infected donors
was inhibited by the addition of anti-IL-6 serum, suggesting that IL-6
overproduction in HIV infection could contribute to B cell hyperstim-
ulation and to hypergammaglobulinemia (Amadori et al., 1989).
Patients with AIDS show an increased frequency of lymphoid malig-
nancies, most of which are high-grade, non-Hodgkin’s I3 cell lympho-
mas. Although these lymphomas are mostly monoclonal, and often
show positivity for the EBV genome, in no case has the existence of the
HIV-1 genome been reported. The increased levels of serum IL-6 and
polyclonal B cell activation may be associated with the increased
frequencies of B cell malignancies seen in AIDS patients. Infection of
the brain with HIV often accompanies neurological manifestations,
clinically (memory loss, dementia, motor deficits, fever, drowsiness,
weakness, and pain) and histopathologically (vasculitis, vascular ne-
crosis, astrogliosis, demyelination, neuron loss, and central nervous
system lymphoma growth). The presence of high levels of IL-6, but not
TNF, in the cerebrospinal fluid of patients with AIDS suggests that
IL-6 may actually be involved in these neurological manifestations of
AIDS (Gallo et al., 1989).
2. Kaposi’s Sarcoma
Kaposi’s sarcoma (KS) is the most frequent tumor seen in individuals
with AIDS. KS cells are of vascular origin and have features in common
with endothelial and smooth muscle cells. The tumor often rapidly
accelerates at the time of opportunistic infection or progression of the
underlying immunodeficiency. AIDS-KS-derived cell lines produce
several cytokines and growth factors, including IL-1, GM-CSF, and
basic fibroblast growth factor (bFGF). Addition of anti-IL-1 or anti-
bFGF sera to AIDS-KS cell lines results in decreased cellular prolifer-
ation, indicating that these factors may be operating as autocrine/
paracrine growth factors for AIDS-KS cells. Also, various AIDS-KS-
derived cell lines have been shown to secrete substantial amounts of
IL-6, to contain intracellular IL-6 by immunoperoxidase staining, and
to display high levels of IL-6 mRNA. AIDS-KS cells express the recep-
tor for IL-6. IL-6 has been shown to stimulate proliferation of AIDS-
KS-derived cell lines (Miles et al., 1990). IL-6 antisense oligodeoxy-
nucleotides decreased IL-6 production by these cells and dramatically
inhibited their growth (Miles et al., 1990). Together, these results
suggest that IL-6 is an autocrine growth factor for AIDS-KS cells.
Oncostatin M is found to be a potent mitogen for AIDS-KS cells (Miles
et al., 1992; Nair et al., 1992).After exposure to oncostatin M, AIDS-KS
cells assumed a spindle morphology, had an increased ability to pro-
liferate in soft agar, and secreted increased amounts of IL-6. Further-
more, antisense IL-6 oligonucleotides inhibited by approximately 50%
the mitogenic effects of oncostatin M, suggesting that both IL-6- and
non-1L-6-dependent mechanisms may be involved in the effects of
oncostatin M on AIDS-KS cells.
HIV tat is a virally encoded, transcription-enhancing molecule,
which can interact with a sequence within the HIV-LTR region to
upregulate viral gene expression. Exogenously added Tat protein en-
tered cells and transactivated the HIV-LTR. It has been reported that
transgenic mice generated with the tat gene under the control of
HIV-LTR developed a KS-like disease similar to the human counter-
part (Vogel et al., 1988).Tat protein is shown to induce IL-6 production
in KS cells and stimulate growth of KS cells (Ensoli et al., 1990). The
Tat-induced increase in IL-6 expression and KS cell proliferation was
specifically inhibited by antisense IL-6 oligonucleotides, suggesting
that at least part of the mechanism by which Tat increases KS cell
proliferation is through an IL-6-dependent mechanism.
E. INFLAMMATORY OR AUTOIMMUNE DISEASES

1. Cardiac Myxoma
The first example of a disease associated with IL-6 overproduction
was cardiac myxoma, a type of benign intraatrial heart tumor (Hirano et
al., 1987). Patients with cardiac myxoma frequently display hypergam-
maglobulinemia and various kinds of autoantibodies and an increase in
acute-phase proteins. As these symptoms disappear after resection of
the tumor, the myxoma cells or products derived from them were
suspected to induce the symptoms. Cultured cardiac myxoma cells
were shown to produce a large amount of IL-6 protein constitutively.
This finding was confirmed by Jourdan et al. (1990), who reported a
case of cardiac myxoma in which after surgical removal of the tumor,
the significantly elevated levels of serum IL-6 returned to undetect-
able levels, with regression of the immunological features. A dose-
dependent relationship is also reported between plasma levels of IL-6,
but not other cytokines (IL-1, TNF-a, IFN-y), and the immunological
features of the patient. This evidence demonstrates that IL-6 is re-
sponsible for the clinical manifestations seen in cardiac myxoma.
2. Rheumatoid Arthritis
Rheumatoid arthritis (RA) patients characteristically show polyclo-
nal plasmacytosis, presence of autoantibodies, and increases in acute-
phase proteins and platelets. These symptoms may be explained by
overproduction of IL-6. In fact, elevated levels of IL-6 can be detected
in the synovial fluid from affected joints and sera of patients with active
RA (Hirano et al., 1988; Houssiau et al., 1988b; Bhardwaj et al., 1989;
Guerne et al., 1989). Significant correlations have also been shown
between the concentrations of synovial IL-6 and IgG, as well as be-
tween serum IL-6 activity and levels of a variety of acute-phase
proteins such as CRP (Houssiau et al., 198813; Hermann et al., 1989).T
cells, B cells, synoviocytes, and chondrocytes have been identified as
sources of IL-6. Several other cytokines, such as IL-1 and TNF, which
are also present in synovial fluid, are potent inducers of IL-6. IL-6 can
contribute to the proliferation of synovial lining cells, which results in
the marked buildup of inflammatory tissue (pannus) in the joints of
patients with RA (Firestein et al., 1990). Inflammatory cytokines and
the network of their interactions may therefore be involved in RA.
Interleukin-6 production was observed in type I1 collagen-induced
arthritis in mice (Takai et al., 1989). An age-associated increase in
serum IL-6 was also observed in MRL/lpr mice, which spontaneously
develop autoimmune diseases with lymphoid hyperplasia associ-
ated with an infiltration of plasma cells, arthritis, hypergamma-
globulinemia, and a high incidence of monoclonal or oligoclonal IgGs
(Tang et al., 1991). Pristane can cause not only plasma cell neoplasias,
but also arthritis in certain mouse strains (Potter and Wax, 1981).To-
gether, these facts suggest that IL-6 may be involved in the develop-
ment of autoimmune arthritis.
3. Castleman’s Disease
Abnormal IL-6 production and polyclonal plasmacytosis have also
been observed in patients with Castleman’s disease (Yoshizaki et al.,
1989). This chronic disease with benign hyperplastic lymphadenopa-
thy is characterized by large lymph follicles with intervening sheets of
plasma cells. The patients show hypergammaglobulinemia and in-
creases in acute-phase proteins and platelets. B blastoid cells in the
germinal centers of such hyperplastic lymph nodes were found to
produce IL-6. Clinical improvement and decrease in serum IL-6 levels
INTERLEUKIN-6 IN BIOLOGY AND. MEDICINE 41
were observed following resection of the hyperplastic lymph node.

Major systemic effects resembling Castleman's disease have been re-
ported in congenitally anemic W / W mice reconstituted with hemato-
poietic cells transfected with the coding sequences of murine IL-6
(Brandt et al., 1990).
4 . Mesangial Proli$erative Glomerulonephritis
Mesangial proliferative glomerulonephritis (MPG) is histologically
characterized by proliferation of mesangial cells. IL-6 is demonstrated
to he a possible autocrine growth factor for rat mesangial cells and to be
constitutively produced by renal mesangial cells in patients with MPG
(Horii et al., 1989; Ruef et al., 1990). Furthermore, IL-6 can be de-
tected in the urine samples of patients with MPG, but not in those of
patients with other types of glomerulonephritis. There is also a correla-
tion between the level of urine IL-6 and the progressive stage of MPG.
5. Psoriasis
Psoriasis is characterized by epidermal hyperplasia, altered epider-
mal maturation, and local accumulation of acute-phase and chronic
inflammatory cells. Various abnormalities have been observed in the
serum and plasma of patients with psoriasis. Increases in CRP and
an-macroglobulin appear related to severity. Significantly elevated
amounts of circulating IL-6 are observed in sera of psoriatics and are
likely to account for the increases in CRP and an-macroglobulin
(Grossman et al., 1989; Neuner et al., 1991).In contrast to normal or
uninvolved skin, keratinocytes in psoriatic lesions are remarkably pos-
itive for IL-6 as detected by immunohistochemistry and in situ hybrid-
ization (Grossman et al., 1989). IL-6 also stimulates the proliferation of
keratinocytes and may account for the hyperkeratosis observed in pso-
riatic plaques. The diminution of hyperkeratosis following therapy
was accompanied by a decrease in IL-6 staining in the psoriatic plaque
(Sehgal, 1990);however, overproduction of IL-6 in skin of mice ex-
pressing the keratin promoter-driven IL-6 transgene did not result in
hyperkeratosis (Truksen et al., 1992).
6. Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a chronic autoimmune dis-
ease involving almost any organ system. One of its major immunologi-
cal abnormalities is B cell hyperactivity. IL-6 levels were elevated in
some of the sera (Swaak et al., 1989) and in the cerebrospinal fluids
(Hirohata and Miyamoto, 1990) of patients with SLE. Patients with
SLE showed increased IL-6 gene transcription by T cells, B cells, and
monocytes (Tanaka et al., 1988; Linker-Israeli and Deans, 1989). IL-6

preferentially stimulates resting SLE B cells (Kitani et al., 1989). SLE
B cells show spontaneous activation by in vitro culture without any
stimulation. The elevated spontaneous in vitro production of IgG by
SLE mononuclear cells is enhanced by exogenous IL-6, and is par-
tially inhibited by neutralizing anti-IL-6 antibodies (Linker-Israeli et
al., 1991).Cultured mononuclear cells from patients with SLE, but not
patients with RA or normal donors, secreted IL-6 after exposure to
ultraviolet light, which may be involved in the exacerbations of SLE
provoked by photosensitivity (Pelton et al., 1992). The mechanism
leading to the constitutive expression of IL-6 in SLE has not yet been
elucidated, It has been reported that SLE patients lack a cell subset
that specifically suppresses IL-6 production (Warrington and Ruther-
ford, 1990). In the plasma of SLE patients, nucleosomes are found as
the major component of circulating DNA (Rumore and Steinman,
1990). Both DNA and nucleosomes have been demonstrated to bind
specifically to the surface of human peripheral blood mononuclear
cells and to stimulate the release of IL-6 (Hefeneider et nl., 1992). IL-6
secretion, as a consequence of DNA and nucleosome interaction with
cell surface binding molecules, may have relevance to the polyclonal
activation of immunoglobulin production seen in SLE patients.
7. Alzheimer’s Disease
Alzheimer’s disease is the most common cause of dementia in the
elderly. The characteristic neuropathological findings are PA4-
containing plaques, neurofibrillary tangles, and amyloid infiltration of
cerebrovascular walls.
There is a significant correlation between PA4 deposition and the
clinical severity of dementia. IL-6 has been implicated in Alzheimer’s
disease (AD), where along with IL-1, it may modulate amyloid protein
precursor synthesis (Griffin et al., 1989; Vandenabeele and Fiers,
1991). A major proteinaceous constituent of senile plaques in AD,
called PA4, is derived from PA4 precursor protein [amyloid precursor
protein (APP)]. Normal secretion of the major amino-terminal part of
the membrane-inserted APP molecules is achieved by cleavage of APP
by a proteolytic enzyme inside the PA4 sequence, thus excluding the
formation of the pathogenic PA4 under normal physiological condi-
tions. Protease inhibitors such as az-macroglobulin (a2-M) and al-
antichymotrypsin prevent normal APP processing in AD, allowing
formation of the pathogenic PA4. a2-M is synthesized by human neuro-
nal cells, but only after stimulation of the cells with IL-6 (Ganter et al.,
1991). Strong immunohistochemical staining for a2-M and IL-6 was
found in senile plaques of AD cortices (Bauer et al., 1991). ( ~ 1 -
Antichymotrypsin that is induced by IL-6 was also a component of
amyloid deposits in neuritic plaques and blood vessel walls from
brains of AD patients.
8 . Cachexia
Animals and humans with chronic infections or cancer may develop
the syndrome of cachexia, which is characterized by severe wasting of
both protein and fat stores. The syndrome is often associated with
elevated serum triglycerides and reduced serum LPL activity. LPL
plays an important role in adipocyte metabolism by hydrolyzing circu-
lating triglycerides to fatty acids for subsequent storage as fat in the
adipocytes. Therefore, a reduction in the activity of LPL contributes to
a decrease in total body fat stores. TNF has been considered as a
mediator of cachexia (Tracey e t al., 1988).Anti-TNF antibodies block
tumor-induced cachexia, but the blocking effect is only partial. Ele-
vated TNF concentrations have generally not been found in cancer
patients with cachexia. On the other hand, introduction of a retroviral
expression vector containing the IL-6 coding sequence into the bone
marrow of mice or introduction of IL-6-transfected Chinese hamster
ovary cells resulted in mice with marked weight loss (Black et al.,
1991).Strassmann et al. (1992) have presented direct evidence of the
contribution of endogenous IL-6 to the development of cachexia. Cir-
culation levels of IL-6 in C-26.IVX-bearing mice correlated directly
with tumor size and the extent of cachexia. In such models IL-6, but
not TNF or IL-1, was detected in the peripheral circulation. If the
primary tumors were resected, mice gained weight and the levels of
IL-6 in the serum were reduced significantly. Moreover, monoclonal
antibody to murine IL-6 (but not anti-TNF antibody) was able to signif-
icantly suppress the development of cachexia in tumor-bearing mice.
Furthermore, it is reported that IL-6 inhibits lipoprotein lipase activity
in adipose tissue and this effect may contribute to the observed weight
loss seen in the tumor-bearing host (Greenberg et al., 1992). The
hypertriglycemia observed in cachexia may be the result of the
increased hepatic production of lipoprotein stimulated by IL-6
(Feingold and Grunfeld, 1992); however, these data are in striking
contrast to the observation that administration of exogenous IL-6 to
mice or other experimental animals does not elicit a weight loss syn-
drome. Perhaps in conjunction with TNF, IL-1, IFN-y, and other as yet
unknown cytokines, IL-6 may play a role in the development of the
cachectic syndrome.
F. OTHERDISEASES
Constitutive production of IL-6 has been demonstrated in renal cell
carcinoma (Miki et al., 1989), ovarian carcinoma (Watson et al., 1990),
pleural mesothelioma (Schmitter et al., 1992), parotid gland adenoma
(Gallo et al., 1992), pheochromocytoma (Fukumoto et al., 1991), and
glioblastoma cells (Van Meir et al., 1990). Patients with these malig-
nancies often exhibit paraneoplastic symptoms, which include fever,
leukocytosis, erythrocytosis, thrombocytosis, hypercalcemia, and ele-
vation of acute phase reactants. Many of the paraneoplastic symptoms
parallel the actions of IL-6.
Elevated IL-6 concentrations are detected in sera of patients with
multiple sclerosis (Maimone et al., 1991; Frei et al., 1991), alcoholic
hepatitis (Hill et al., 1992a; Sheron et al., 1991),acute hepatitis (Sun et
al., 1992), polyarteritis nodosa (Nakahama et al., 1992), keloid (Mc-
Cauley et al., 1992), and HTLV-1-associated myelopathy (Ohbo et al.,
1991; Nishimoto et al., 1990). Patients with these diseases sometimes
manifest many aspects of the acute-phase response and systemic B cell
activation, which may be explained by actions of IL-6.
Interleukin-6 may be an important mediator in the pathogenesis of
autoimmune insulin-dependent diabetes mellitus (Bendtzen et al.,
1989; Cambell et al., 1989, 1991), thyroiditis (Bendtzen et al., 1989),
and Paget’s disease (Roodman et al., 1992).
High-level expression of IL-6 mRNA was detected in active in-
flammatory bowel disease specimens from ulcerative colitis and
Crohn’s disease patients (Stevens et al., 1992) and in atherosclerotic
lesions of WHHL rabbit aortae, which are strikingly similar to those
observed in human familial hypercholesterolemia (FH)(Ikeda et al.,
1992a).
Levels of IL-6 were significantly elevated in the bronchoalveolar
lavage fluid of patients with symptomatic compared with asymptom-
atic asthma (Mattoli et al., 1991; Broide et al., 1992).
In contrast, a recent report shows that IL-6 may act as an agent that
downregulates an inflammatory response. Denis (1992) examined the
role of IL-6 in the development of chronic lung inflammatory condi-
tions, using a mouse model of hypersensitivity pneumonitis estab-
lished by intranasal instillation of the thermophilic actinomycete.
Neutralization of endogenous IL-6 by anti-IL-6 antibody brought
about a significant increase in fibrosis. Conversely, direct IL-6 intratra-
cheal infusion was associated with a diminished fibrotic response. This
decrease in fibrosis was shown to be the result of the decreased neutro-
phi1 influx and the inhibitory action of IL-6 on the production of TNF,
which plays an important role in mouse hypersensitivity pneumonitis.
INTERLEUKINS I N BIOLOGY AND MEDlCINE 45
Diseases associated with abnormal IL-6 production are summarized

in Table IV.
G. INTERLEUKIN-6TRANSGENIC MICE
Transgenic animals or animals engrafted with a tumor genetically
engineered to produce a given cytokine provide models for studying
the in vivo effects of cytokines. To analyze the biological effects of very
TABLE IV
INTERLEUKIN-6 AND CLINICAL DISORDERS
Acute inflammatory disorders

Meningitis
Intrauterine infection
Acute transplant rejection
Burns
Surgical trauma
Chronic diseases
Rheumatoid arthritis
Mesangial proliferative glomerulonephritis
Psoriasis
Castleman’s disease
Alzheimer’s disease
Systemic lupus erythematosrls
Autoimmune insulin-dependent diabetes
Thyroiditis
Multiple sclerosis
Alcoholic hepatitis
Acute hepatitis
Bronchial asthma
Paget’s disease
Polyarteritis nodosa
Crohn’s disease
Scleroderma
Cachexia
Keloid
HTLV-associated myelopathy
Arteriosclerosis
Neoplasms
Multiple myeloma
Leukemia
Post-transplant lymphoproliferative disorders
Kaposi’s sarcoma
Renal cell carcinoma
Pheochromocytoma
Pleural mesothelioma
Cardiac myxoma
Parotid eland adenoma
high and continuous levels of IL-6, IL-6 transgenic mice were gener-
ated. The IL-6 transgenic mice (C57BL/6) were produced using the
human IL-6 genomic gene fused with the human immunoglobulin
heavy chain enhancer to ensure a high level expression of IL-6 in B
lineage cells (Suematsu et al., 1989). In these IL-6 transgenic mice a
fatal plasmacytosis, histologically indistinguishable from plasmacy-
toma, was generated. High concentrations of human IL-6 and a poly-
clonal increase in IgGl were detected in the sera of all transgenic mice;
however, the plasma cells were not transplantable to syngeneic mice
and did not contain obvious c-myc gene rearrangements, which are
observed in almost all pristane-induced plasmacytoma cells. Suscepti-
bility to plasmacytoma development is genetically determined and
most inbred strains other than BALB/c are resistant. Backcrossing the
C57BL/6 IL-6 transgenic mice to BALB/c induced transplantable plas-
macytomas with myc translocation (Suematsu et al., 1992).
The other interesting findings in the IL-6 transgenic mice are the
generation of MPG and the increase in mature megakaryocytes in the
bone marrow. The former evidence taken together with the clinical
and experimental data described in the previous section indicate that
abnormal IL-6 expression plays a critical role in the generation of
MPG. The latter evidence is in complete agreement with the recent
findings that IL-6 induces the maturation of megakaryocytes as a thom-
bopoietic factor in uitro and induces an increase in platelet number in
both mice and monkeys.
The effects of IL-6 in uiuo were assessed b y inoculating into nude
mice Chinese hamster ovarian (CHO) cells that were transfected with
the murine IL-6 gene (Black et al., 1991). Nude mice bearing CHO
cells expressing IL-6 developed hypercalcemia, leukocytosis, throm-
bocytosis, and cachexia, suggesting that increased circulating concen-
trations of IL-6 in patients with malignant disease may contribute to a
number of paraneoplastic syndromes including hypercalcemia, ca-
chexia, leukocytosis, and thrombocytosis.
It has been demonstrated that mice transplanted with bone marrow
cells infected with an IL-6-producing retrovirus develop a fatal myelo-
proliferative disease within 4 weeks of engraftment (Hawley et a1.,
1992).The mice manifest elevated peripheral leukocyte counts with a
predominance of neutrophilic granulocytes, increased mesangial cell
proliferation in the kidney, frequent liver abnormalities, and marked
alterations in plasma protein levels.
To explore the role of IL-6 in skin, transgenic mice were constructed
by using a human keratin 14 promoter to express IL-6 in the basal cells
of stratified squamous epithelia (Truksen et al., 1992). Mice expressing
the K14-IL-6 transgene were smaller than normal and exhibited re-
tarded hair growth. IL-6 expression did not lead to enhanced epider-
mal proliferation but it did result in a thicker stratum corneum without
leukocytic infiltration, making it unlikely that it has direct proinflam-
matory activity in skin. The promotion of increased stratum corneum
formation may help to counteract otherwise deleterious effects, such as
accelerated growth of basal epidermal cells and subsequent sloughing
of the differentiating cells from the skin surface, observed in psoriatic
skins. Alternatively, it may be that only in combination with other
factors such as IFN-y, GM-CSF, and IL-1, is this cytokine capable of
mediating proinflammatory effects in the skin.
VII. interieukin-6 as a Diagnostic Marker

Interleukin-6 may be a diagnostic cytokine for intraamniotic infec-
tion (Romero et al., 1992). Second- or third-trimester amniotic fluid
contained detectable but low levels of IL-6 (range, 50-1500 pg/ml). In
preterm labor associated with intraamniotic infection there was a dra-
matic increase in the concentration of IL-6, up to 5 pg/ml (Romero et
al., 1990; Santhanam et al., 1991a). Patients with raised IL-6 concentra-
tions but without demonstrable infection showed histological evi-
dence of chorioamnionitis and/or failed to respond to tocolysis (phar-
macological inhibition of labor). These findings indicate that the
measurement of amniotic fluid concentrations of IL-6 could be ofvalue
in the diagnosis of microbial invasion of the amniotic cavity. Patients
with an increased amniotic fluid IL-6 level, despite negative amniotic
fluid cultures, are at risk for histological chorioamnionitis and preterm
delivery.
Interleukin-6 is an unspecific marker for the inflammatory state and
does not allow discrimination of various inflammatory diseases;
however, Heney et al. (1992) have measured plasma IL-6 to evaluate
its diagnostic value in the assessment of febrile neutropenia and to
study its relationship with CRP. There was a statistically significant
difference between median admission IL-6 levels of patients with
gram-negative and -positive infections and unexplained fevers. These
groups could not be differentiated by CRP levels alone. The measure-
ments of plasma IL-6 on admission provides a more sensitive pre-
dictive marker than does CRP of subsequent disease severity and may
help to differentiate diagnostic groups of children with febrile neu-
tropenia.
Furthermore, IL-6 may be a diagnostic aid during the first hours of an
inflammatory state, particularly if CRP levels had not yet increased.
Interleukin-6 is also a prognostic factor in multiple myeloma and

renal cell carcinoma. Myeloma patients whose IL-6 serum concentra-
tion at the time of diagnosis was less than 7 pg/ml showed significantly
longer survival than patients whose IL-6 level was 7 pg/ml or higher.
The respective 50%survival rates were 53.7 months as compared with
only 2.7 months (Ludwig et al., 1991). Also, renal cell carcinoma pa-
tients with high serum IL-6 levels had a shorter time between the
diagnosis of their primary tumor and the development of metastases, as
well as a shorter survival (Blay et al., 1992). It has been shown that the
measurement of urinary IL-6 is a helpful tool for monitoring the pro-
gression of IgA nephropathy (Dohi et d., 1991).
Interleukin-6 measurements may be useful in monitoring early re-
jection in transplant patients. Van Oers et al. (1988) demonstrated that
IL-6 was increased in both blood and urine at the time of rejection
following renal transplantation. In liver transplantation, it has been
reported that IL-6 in bile is useful as a marker of acute rejection
(Umeshita et al., 1992).
VIII. Clinical Application of Interleukin-6

A. TREATMENT OF MYELOSUPPRESSION AND THROMBOCYTOPENIA
Neutropenia and thrombocytopenia are major factors contributing to

morbidity and mortality after radiotherapy or chemotherapy of cancer.
IL-6 may be therapeutically useful in the treatment of radiation- or
chemotherapy-induced myelosuppression and thrombocytopenia
(Burstein et al., 1992; Herodin et al., 1992). It has been shown that
rIL-6 stimulates multilineage hematopoiesis and accelerates recovery
from radiation- or chemotherapy-induced hematopoietic depression
(Patchen et al., 1991; Takatsuki et al., 1990).IL-6 has been also shown
to stimulate megakaryocyte maturation in uitro and to produce in-
creased peripheral platelet levels in uiuo. Considering the fact that
rhIL-3 markedly expands the pool of megakaryocyte progenitors but
lacks significant stimulatory activity on the terminal phase of platelet
production, whereas rhIL-6 causes a dose-dependent increase in
blood platelets, the sequential administration of rhIL-3 and rhIL-6
represents a novel and powerful strategy to stimulate thrombopoiesis
in uiuo, and may have therapeutic potential in conditions with de-
creased platelet production (Geissler et al., 1992).
B. CANCER
TREATMENT
Application of cytokines has shown promise in cancer treatment.
Many cytokines are now in clinical trials. IL-6 has been demonstrated
to have potent antitumor activity in certain types of tumors. Adminis-
tration of rIL-6 resulted in a reduction in the number of microme-

tastases from sarcomas and adenocarcinomas in mice (Mul’e et al.,
1990).This antitumor activity may be associated with the development
of specific cytotoxic T cells, because IL-6 induces tumor-specific cy-
totoxic T lymphocyte generation via the activation of helper T cells in
uiuo (Kitahara et al., 1990; Mul’e et al., 1992). rIL-6 also augments the
antibody-dependent cellular cytotoxicity (ADCC) activity of human
peripheral blood mononuclear cells using antibodies to human tumor
antigens and human tumor cells as targets, suggesting a potential role
for IL-6 in combination with anticancer antibodies for cancer therapy
(Tsang et al., 1991).
Because of the very short in uiuo half-life of rIL-6, continuous infu-
sion or regular injections are necessary for obtaining the significant
effects, and this may cause systemic toxicity. To avoid this drawback
“tumor cell-targeted cytokine gene therapy” has been developed, in
which the tumor cells are genetically engineered to produce a given
cytokine in uitro and their injection into mice provides a locally en-
hanced cytokine concentration (Russell, 1990). Tumor cell-targeted
cytokine gene therapy in animal trials has been successfully used with
IL-2, IL-4, IFN-y, TNF-a, and IL-6, providing therapeutic potential
against human cancer. IL-6 transfection into the high-metastatic, low-
immunogenic D122 clone of Lewis lung carcinoma resulted in a signif-
icantly lower metastatic competence of the tumor cells in syngeneic
C57B1/6 mice. Reduction of their tumorigenic properties and suppres-
sion of their metastatic competence were correlated with the extent of
IL-6 production (Porgador et al., 1992). Thus, it seems that the pros-
pects for antimetastatic immunotherapy by cellular vaccination of tu-
mor cells genetically manipulated to express IL-6, either alone or in
combination with genes of the MHC or other cytokines, deserve inves-
tigation.
In the therapy of malignant disease, suppression of malignancy by
inducing differentiation is an alternative approach to the use of anti-
cancer compounds that kill normal cells as well as tumor cells. The fact
that IL-6 promotes differentiation of myeloid leukemias suggests the
potential therapeutic usefulness of IL-6 in certain myeloid leukemia
cells (Givon et al., 1992). In both transplantable and radiation-induced
acute myelocytic leukemia (AML) in SJL/J mice, administration of
IL-6 reduced the incidence of leukemia development and increased
survival. In addition, in uitro liquid cultures of leukemic blood cells
obtained from AML patients showed that IL-6 inhibited growth and
decreased the proportion of blasts with an increase in more mature
myeloid elements; however, IL-6 was suspected to act as a growth
factor for AML blasts of certain AML patients. To determine the possi-
bility of using IL-6 in the treatment of human AML, the in uitro action
of IL-6 on growth and differentiation of AML should be examined in
both liquid and semisolid cultures.
IX. Clinical Application of Interleukin-6 Inhibitors

A. ANTI-INTERLEUKIN-6ANTIBODY
A clinical trial in which anti-IL-6 antibodies were used for the ther-
apy of multiple myeloma was performed by Klein and his colleagues
(1991). Injection of anti-IL-6 antibodies into multiple myeloma pa-
tients with terminal disease and extramedullary proliferation com-
pletely blocked myeloma cell proliferation in uiuo and completely
inhibited the serum IL-6 bioactivity and serum CRP levels. The clini-
cal status of patients improved throughout treatment and no major side
effects were observed. Even in patients with advanced or terminal
disease, in uitro myeloma cell proliferation was found to be dependent
on IL-6. The reduction in serum calcium levels during treatment is
inconsistent with data showing a role for IL-6 in bone resorption in
vitro (Bataille et al., 1992).
B. CYTOKINES AND CHEMICALS INHIBITING

INTERLEUKIN-6 SYNTHESIS
Corticosteroids and estrogens are potent inhibitors of IL-6 produc-
tion as a result of their inhibition of IL-6 gene transcription. The
inhibitory effect of corticosteroids on myeloma growth seems to be
mediated by a steroid-induced decrease in IL-6 expression. Adria-
mycin, vincristine, and cyclophophamide, used in the treatment of
multiple myeloma, are reported to suppress the release of IL-6 from
LPS-stimulated human peripheral blood mononuclear leukocytes
(Hasan et al., 1992). IL-4 has also been shown to interfere with growth
of plasmacytoma cells by blocking endogenous IL-6 synthesis (Taylor
et al., 1990; Herrmann et al., 1991). Retinoic acid downregulates the
number of IL-6Rs on the myeloma cell line AF10, a variant that was
cloned from U266, and, correspondingly, inhibits cell proliferation
(Side11 et al., 1991). The antiproliferative action of retinoic acid on
AFlO cells may be caused by reduction of IL-6R expression and sub-
sequent inhibition of IL-6-mediated autocrine growth.
B chronic lymphocytic leukemia (B-CLL)and hairy leukemia (HCL)
produce IL-6, which may induce positive feedback growth loops.
IFN-a abrogates IL-6-induced proliferation of HCL and B-CLL cells
in uiuo (Heslep et al., 1990). Taken together, these data suggest that
IL-4, retinoic acid, and IFN-a may exert therapeutic effects in these
malignancies by blocking the IL-6.IL-6R autocrine loop.
Interleukin-4 has recently been shown to inhibit the secretion of
proinflammatory cytokines such as IL-1, TNF, and IL-6 by activated
PBMCs, monocytes/macrophages, or synovium (Briolay et al., 1992).
IL-4 strongly inhibits the production of proinflammatory cytokines by
rheumatoid synovium, at both the protein and mRNA levels (Miossec
et d.,1992).IL-4 also has the ability to inhibit cytokine-induced bone
resorption in uiuo (Watanabe et aZ., 1990). The inhibition of proin-
flammatory cytokine production by IL-4 might provide the rationale
for the clinical use of IL-4 either systemically or locally at the site of
inflammation in chronic inflammatory diseases such as rheumatoid
arthritis.
C. CHIMERIC TOXINS
Ira Pastan and his colleagues developed a chimeric toxin in which
IL-6 was fused to a mutant form of psuedomonal exotoxin (Siegall et
al., 1988).The chimeric toxin has been previously shown to specifi-
cally kill malignant hepatic, prostatic, epidermoid, and myeloma cell
lines in uitro (Siegall et al., 1990, 1991).The chimeric toxin is being
considered for a clinical trial in treating multiple myeloma (Kreitman
et al., 1992), in either phase I in uiuo treatment or ex uiuo purging of
myeloma cells in autologous transplant protocols. Current problems in
the use of recombinant fusion toxins in humans are the killing of
numerous normal cells, particularly hepatocytes, that express IL-6
receptors and the appearance of antitoxin antibodies in some patients.
X. Conclusions
Interleukin-6 may be described as a double-edged sword. There can
be little doubt that IL-6 plays a pivotal role in hematopoiesis, immune
reactions, and acute-phase responses; however, it has been demon-
strated that the abnormal expression and dysregulation of IL-6 are
involved in the pathogenesis of certain diseases. Therefore, the inhibi-
tion or modulation of IL-6 could have profound therapeutic benefits,
although in most diseases it is apparent that more than one cytokine is
involved and that the full clinical manifestations of the diseases result
from the dysregulated cytokine network. It is now clear that blockade
of IL-6 function can inhibit myeloma cell proliferation and improve
the clinical status of patients with multiple myeloma.
The cell biology of the intracellular events that link transduction to
gene regulation is an important area, and work on these topics may
help us understand such phenomena as multifunction of IL-6 (acute-

phase protein synthesis from hepatocytes, neural outgrowth of PC 12
cells, differentiation to macrophages, and immunoglobulin production
in B cells) and bidirectional effects of cell growth (growth-inhibitory
and -stirnulatory effects) depending on the cell type. Furthermore,
selective inhibition of transmembrane signaling events may have ther-
apeutic potential, as demonstrated in cyclosporin and FK506, which
inhibit the synthesis of NFAT-1, a transcription factor involved in IL-2
gene expression in T cells. Much work remains to be done in defining
the roles for IL-6 in embryogenesis and development, because IL-6 is
expressed very early in embrogenesis. Through the development of
knockout mice lacking IL-6 or the 1L-6 receptor complex, many of the
unsolved issues about the roles of IL-6 in normal and different patho-
logical conditions should be resolved in the near future.
ACKNOWLEDGMENTS
We thank Ms. K. Kubota and Ms. K. Ono for their excellent secretarial assistance.
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ADVANCES IN IMMUNOLOGY, VOL.

Interleukin-6 in Biology and Medicine

SHIZUO AKIRA,. TETSUYA TAGA,' AND TADAMITSU K l S H l M O T W

II. Historical Overview

B cell stimulatory factor-2 (BSF-2)

111. Structure and Expression of Interleukin-6

between these molecules (Leutz et al., 1989). The two disulfide

FIG.1. Schematic ternary structure of interleukin-6. IL-6 protein is predicted to be

B. INDUCERS AND PRODUCERS

Interleukin-6 is produced by many different cell types including

Cell Type Inducer

regulation of IL-6 production varies, depending on the cell type. Lipo-

peating AU-rich sequences in its 3' untranslated region, which are

GRE GRE AP-1 CRENF-IL6 C-fOERCE N F - a TATA

the 14-bp palindrome are present. An NF-KB binding motif is also

and acute-phase protein genes (Natsuka et al., 1992).NF-IL6 has been

RB are considered to be tumor suppressor proteins that are frequently

IV. Interleukin-6 Receptor

at the carboxyl-terminal end. This homologous module comprises two

cytokine receptor family module in its extracellular region retains IL-6

the IL-6R complex comprises two functionally different membrane

subunit of the LIF-R complex (Gearing et al., 1991). This converter

duction and may be a component of the IL-11R complex (Y.-C. Yang et

No enzymatic activities or sequence motifs known for signal trans-

receptor to nuclear factor, an ultimate target of the IL-6 signal. NF-IL6

V. Biological Function of Interleukin-6

clonal antibodies (Garman et al., 1987; Lotz et al., 1988; Uyttenhove

were under the control of a specific factor(s) called thrombopoietin.

ceptor), indicating the functional differentiation into mature macro-

Inflammation is accompanied by the acute-phase response which is

1988). An IL-6-mediated increase in serum acute-phase proteins was

synthesis of acute-phase proteins by hepatocytes (Snyers et al., 1990;

and TNF-stimulated collagenase and PGE2 production by chondro-

manner (Finkel et al., 1992). The nitric oxide synthase inhibitor N G -

shown to work as an autocrine or paracrine inflammatory cytokine.

however, the role of IL-6 in embryogenesis awaits further experi-

Effect on €3 cells Immunoglobulin production

VI. Interleukin-6 and Disease

and Boyce, 1962). Indomethacin inhibits plasmacytogenesis (Potter

tutively produced IL-6 owing to the insertion of an intracisternal A

cyclosporin A enhanced transcription of the IL-6 gene suggests that

onts of P. berghei (Vreden et al., 1992). IL-6 is also shown to directly

Increased levels of IL-6 have been reported in the serum of HIV-

E. INFLAMMATORY OR AUTOIMMUNE DISEASES

were observed following resection of the hyperplastic lymph node.

monocytes (Tanaka et al., 1988; Linker-Israeli and Deans, 1989). IL-6

Diseases associated with abnormal IL-6 production are summarized

Acute inflammatory disorders

VII. interieukin-6 as a Diagnostic Marker

Interleukin-6 is also a prognostic factor in multiple myeloma and

VIII. Clinical Application of Interleukin-6

Neutropenia and thrombocytopenia are major factors contributing to

tration of rIL-6 resulted in a reduction in the number of microme-

IX. Clinical Application of Interleukin-6 Inhibitors

B. CYTOKINES AND CHEMICALS INHIBITING

help us understand such phenomena as multifunction of IL-6 (acute-

Heinrich, P. C. (1987).Recombinant human B cell stimulatory factor 2 (BSF-2IIFN-p

R. M., Sehgal, P. B., and May, L. T. (1989). IL-GIIFN-pB in synovial effusions of

S. I. (1992). Cytokines in symptomatic asthma airways. J . Allergy Clin. Immunol. 89,

produced by bone and modulated by parathyroid hormone. J. Bone Miner. Res. 4,

terization of IL-6 receptor expression by monoclonal and polyclonal antibodies.

chorionic gonadotropin release through IL-6 receptor on human trophoblasts. J . Clin.

Venuta, S. (1990). Expression of an exogenous interleukin 6 gene in human Epstein

This article was accepted for publication on 10 February 1993.