Proinflammatory Cytokines

Marc Feldmann* and Jeremy Saklatvala

Cytokine and Cellular Immunology Division, Kennedy Institute of Rheumatology, 1 Aspenlea Road, Hammersmith, London, W6 8LH, UK * corresponding author tel: 44 (0)208 383 4406, fax: 44 (0)208 563 0399, e-mail: m.feldmann@ic.ac.uk DOI: 10.1006/rwcy.2000.02004.

SUMMARY
As inflammation is a complex series of events, involving many cell types, it is evident that a great many molecules are encompassed by the term `proinflammatory cytokines'. The aim of this chapter is to provide an introduction to these molecules and a guide to this complex field. We have chosen to structure this chapter on a functional basis, reviewing the principles of innate (natural) immunity and the cell types most closely involved, and their molecular products. Details are found in other chapters.

INTRODUCTION
In the context of host defense and pathology, proinflammatory cytokines which are produced very early in the response to multiple stresses are important in being involved in both innate and acquired immunity. The term `proinflammatory cytokines' includes many cytokines characterized as being inducible and belonging to different families, including IL-1, IL-6, TNF, and the subsequently discovered molecules of the TNF family with related properties that promote inflammatory host reactions such as secreted lymphotoxin  (also known as TNF ), the heterotrimeric membrane-bound lymphotoxin , LIGHT, CD40 ligand, Fas ligand, CD30 ligand, CD27 ligand, 4-1BB ligand, and the Ox40 ligand (Beutler and Cerami, 1989; Kishimoto et al., 1992; Smith et al., 1994; Dinarello, 1998).

Other critical proinflammatory cytokines are IFN , IL-2, both products chiefly of TH1 cells as well as IFN/ (Goeddel et al., 1981; Gray et al., 1982; Smith, 1988). The interferons are intimately concerned in innate immunity, and are also involved in helping to induce the acquired immune response. For example IFN is the most potent activator of antigen presentation and HLA class II expression, all interferons (, ,  ) are powerful upregulators of HLA class I. The potency of interferons in activating immunity is illustrated by the fact that of all the cytokines tested so far only interferons, if abnormally expressed locally in a transgenic mouse, are capable of inducing a T cell-dependent autoimmune disease, such as diabetes mellitus (Sarvetnick et al., 1988). Chemokines, exerting their major function of chemoattracting and activating leukocytes, are also intimately involved in innate immunity and the proinflammatory response. Chemokines are the most numerous family of cytokines (Kunkel et al., 1996). There is a considerable literature showing that inflammation in excess is detrimental, and that excessive production and release of TNF and IL-1 may lead directly to pathology. However, there is also abundant evidence that proinflammatory cytokines are very important for the activation of the acquired immune response, which, while usually beneficial, can also lead to pathology such as detrimental autoimmune responses. Recruitment of bloodborne cells such as neutrophils and macrophages to a site of injury can lead to removal of damaged and dead cells, but in excess these cells may cause further tissue damage by release of granule contents, enzymes, and

292 Marc Feldmann and Jeremy Saklatvala the production of free radicals (Springer, 1994). The synthesis of new connective tissue components is important in tissue repair, but in excess this can lead to fibrosis with scarring, deformities, vascular obstruction, etc. (Border and Noble, 1994). Thus the impact of the proinflammatory cytokines in any given situation is varied and depends on many other factors, both qualitative and quantitative. The most important determinants of proinflammatory cytokine activity are their concentration, duration of expression, and also the level of expression of their cell surface receptors. Inflammation is also modulated by the concentration of cytokine inhibitors, defined in the broadest sense. In any inflammatory site there are a mixture of other signals, cytokine and others present in the area, which may synergize (e.g. TNF and IL-1) or antagonize (TNF and IL-10). Thus it is difficult to determine the net effect of cytokines at an inflammatory site at any point in time (Feldmann et al., 1996). This makes it exceedingly difficult at times to predict in vivo effects and roles of cytokines based on in vitro experimental models. Furthermore, any attempt to understand the role of a given cytokine by only assaying its mRNA by RT-PCR (which is increasingly popular) will not reveal the function of a cytokine in a given situation, as mRNA alone does not reflect the functional effect of the cytokine in its local context.
Figure 1 Interactions of innate and acquired immunity.
ANTIGEN PRESENTATION OF PEPTIDE FRAGMENTS BY MHC
PEPTIDES LIPID CARBOHYDRATE

ACTIVATES INNATE IMMUNITY via Toll, complement mannose receptors etc.

INFLUENCES TYPE OF RESPONSE

AND

ENHANCES IMMUNOGENICITY

APC MAKES IL-12 T, NK IFN

NATURAL T CELLS MAST CELLS MAKE IL-4, ?IL-7

Th1/Tc1 IFN / IL-2

Th2/Tc2 IL-4, IL-5

NATURAL (INNATE) IMMUNITY

The innate immune response is the `preprogrammed' reaction to microorganisms, which is independent of antibodies and lymphocytes. It antedates and helps trigger adaptive lymphocyte-dependent immunity, and acts as a `frontline' emergency response in the days before amplification of specific T cell and antibody responses becomes effective. In the case of bacteria or parasites it involves their innate recognition by phagocytic cells (macrophages and granulocytes) and activation of complement (Figure 1). There are also innate cellular reactions to viral infection, especially the production of interferons. Other leukocytes such as basophils, mast cells, eosinophils, and NK cells are also involved in the innate immune response. There is an intimate interplay of the innate and adaptive immune systems, and the boundary between them can be hard to establish. There is increasing evidence that for an immune response to be effectively established, an inflammatory response is needed to help the process along. This inflammatory response is due to the inducing components of the microbial

agents, be they bacteria, viruses or parasites, or with vaccination is due to adjuvants. The role of adjuvants are to increase antigen persistence and induce the production of cytokines, thus mimicking the effects occurring spontaneously with microorganisms. Some of the most potent adjuvants actually are inactivated microbial organisms. Recently, this effect of microorganisms in inducing `damage' as a prelude to the generation of an immune response has been termed the `danger hypothesis' (Matzinger, 1994). Phagocytic cells have receptors for microbial molecules, particularly cell wall components, which activate phagocytosis and killing of the organism, and also stimulate the production of mediators including proinflammatory cytokines. These receptors tend to have a broad specificity for complex microbial lipids, carbohydrates, and proteins and have been called pattern-recognition receptors (Madzhitov and Janeway, 1997). These receptors, together with plasma protein constituents that recognize microbial structures are summarized in Table 1. While some receptors (such as the mannose receptor and scavenger receptors) trigger phagocytosis, others activate cells for mediator production. The best known of the latter is CD14, a receptor for the endotoxin of gramnegative bacteria, lipopolysaccharide (LPS) together with toll-like receptor 4 (TLR4). The main result of the immediate cell activation caused by microorganisms (besides phagocytosis) is production of cytokines and other mediators which recruit more leukocytes from the circulation. Bacteria and yeasts directly activate complement. This is brought about by the mannose-binding protein of serum which is associated with a serine proteinase that cleaves C2, C3, and C4. Complement activation contributes to the innate response by

Table 1 Pattern recognition molecules of the innate immune system Protein family C-type lectins Humoral Cellular Plasma protein Macrophages, dendritic cells Macrophages, dendritic cells Macrophages, dendritic cells NK cells NK cells Leucine-rich proteins Macrophages, epithelial cells Monocytes, others B cells Scavenger receptors Macrophages Macrophage subset  T cells (cattle) Pentraxins Lipid transferases Integrins Plasma protein Plasma protein Plasma protein Plasma protein Macrophages, dendritic cells, NK, T cells Collectins (MBL) Macrophage C-type lectin Macrophage mannose receptor DEC 205 NKR-P1 Ly49 CD14 TOLL homolog RP 105 Macrophage scavenger receptor MARCO WC1 C-reactive protein Serum amyloid P LBP BPIP CD11b,c : CD18 Bacterial and viral carbohydrates GalNAc receptor Terminal mannose Terminal mannose Unknown CHO MHC class I (CHO?) LPS Unknown ligand Unknown Bacterial cell walls Bacterial cell walls Unknown Phosphatidyl choline Bacterial cell walls LPS, other LS LPS, other LS LPS Opsonization, activation of complement (lectin pathway) Induces macrophage tumoricidal activity Phagocytosis Phagocytosis Cytolytic function, IFN- secretion Inhibition of activation Signals cells Signals NF B Mitogenic for B cells Phagocytosis Unknown Unknown Opsonize, activate complement Opsonize, activate complement Bind LPS, transfer to CD14 Bacteriocidal activity Signal cells, phagocytosis Drickamer and Taylor, 1993; Sastry and Ezekowitz, 1993 Suzuki et al., 1996 Sahl, 1992 Jiang et al., 1995 Yokoyama, 1995 Yokoyama, 1995 Ulevitch and Tobias, 1995; Wright et al., 1990
a

Site of expression

Example

Ligands

Known functions

Reference

Miyake et al., 1995 Krieger and Herz, 1994 Elomaa et al., 1995 Walker et al., 1994 Gewurz et al., 1995 Emsley et al., 1994 Schumann et al., 1990 Elsbach and Weiss, 1993 Ingalls and Golenbock, 1995

a A mammalian homolog of Drosophila TOLL protein (R. Medzhitov, C. A. Janeway Jr, unpublished data); BPIP, bacterial permeability increasing protein; CHO, carbohydrate; GalNAc, N-acetylgalactosamine; LBP, LPS-binding protein; LPS, lipopolysaccharide; LS, liposaccharide; MBL, mannon-binding lectin. Reproduced with permission from Medzhitov and Janeway (1997) Current Opinion in Immunology 9, 49.

294 Marc Feldmann and Jeremy Saklatvala generating additional chemotaxins as well as by damaging and opsonizing the microorganisms. Viral infection of cells causes production of interferons which induce antiviral responses in neighboring cells, protecting them from infection. Viral infection can also directly activate protein kinase R, which inhibits protein synthesis so frustrating viral replication. NK cells recognize and kill cells infected with certain viruses. Besides being an immediate defense, the innate immune response facilitates acquired immunity in several ways. First, cytokine production promotes phagocytosis and antigen presentation by dendritic cells (adjuvants work partly by provoking cytokine production). Secondly, the proinflammatory cytokines IL-1, IL-6, and TNF are co-mitogenic for lymphocytes. Thirdly, complexing of complement fragment C3d with antigen facilitates activation of B cells, because co-ligation of receptors lowers the threshold for antigen stimulation, so facilitating the humoral response and induction of memory cells (Fearon and Locksley, 1996). The innate immune response is phylogenetically ancient and it is interesting that some viruses have acquired cytokine and cytokine receptor genes which they apparently use to circumvent host defense. These include soluble receptors for IL-1, TNF, interferons, and chemotactic cytokines, and Epstein-Barr virus IL-10-like protein. A gross manifestation of the cellular activation in both innate and acquired immune responses is inflammation (Fearon and Locksley, 1996). The proinflammatory cytokines from mononuclear phagocytes drive many of the processes underlying this complex tissue response. intracellular domain is homologous to a cytoplasmic region of the IL-1 type I receptor, and utilize the adapter protein MyD88. The Toll-like proteins use IL-1R signaling components MyD88, IRAK, and TRAF6 (Kopp and Medzhitov, 1999; Zhang et al., 1999). Consequently LPS signaling is probably very similar to IL-1 and TNF signaling. Interestingly, bacterial peptidoglycan and lipotechoic acid, which also bind to CD14, also activate cells via Toll-like protein 2 (Schwander et al., 1999). The mammalian Toll proteins are probably a large family that may sense other as yet unidentified microbial products. There are probably native (mammalian) ligands these, too, are unknown. Macrophage activation caused by microbial products is augmented by autocrine action of cytokines (e.g. TNF and GM-CSF). Macrophage activation is also augmented by T cell products such as IFN and IL-2.

MACROPHAGES ARE A MAJOR SOURCE OF PROINFLAMMATORY CYTOKINES

As discussed above, proinflammatory cytokines include inducers of the immune and inflammatory response, with many molecules involved in both processes. Macrophages are capable of producing a plethora of cytokines, including TNF, IL-1, IL-6, IL-12, IL-15, IL-18, chemokines such as IL-8, MIP1, MIP-1,MCP-1, interferons, etc.

MACROPHAGE ACTIVATION
The central features of the innate response are the spontaneous phagocytosis of microorganisms and the generation of cytokines and other inflammatory mediators by the macrophage. The most studied microbial molecule sensed by macrophages is the lipopolysaccharide (LPS) of gram-negative bacteria, also called bacterial endotoxin (Ulevitch and Tobias, 1999). It binds to CD14 on the macrophage (or monocyte) surface, and binding is enhanced by a plasma LPS-binding protein (LBP). The LPS/CD14 complex then activates Toll-like proteins 2 and 4 (Yang et al., 1998; Chow et al., 1999; Kopp and Medzhitov, 1999). The Toll proteins are transmembrane signaling proteins originally discovered in Drosophila. They activate NF B and part of their

IL-1 and TNF

There are two IL-1 genes,  and  . IL-1 accounts for about 10%, and IL-1 for 90% of IL-1 protein made by LPS-activated human monocytes. They are made as cytoplasmic precursors. IL-1 is released from the cell after processing by IL-1-converting enzyme, ICE (also known as caspase 1). IL-1 processing and release is not understood. Some remains surface associated. A related protein is the IL-1 receptor antagonist IL-1Ra. This binds IL-1 receptors without activating them. It is made by monocytes and other cells, and one form is released via the normal secretory pathway. The IL-1Ra gene is also spliced to produce two intracellular forms, the role of which is not understood. There are two TNFs, TNF is made by macrophages, and the related lymphotoxin  (also called TNF) chiefly by activated T cells.

Proinflammatory Cytokines IL-1, IL-1 , and TNF are very similar in their inflammatory effects. The major difference in their biological actions is that TNF, in addition to being connected to inflammatory intracellular signaling pathways, is also linked to apoptotic pathways via the death domain of the p55 TNFR. IL-1R type I (the signaling receptor) has no death domain. The immediate effect of IL-1 and TNF is to upregulate adhesion molecules (E-selectin, ICAM-1, V-CAM) on vascular endothelial cells and to stimulate production of chemotactic cytokines (chemokines) by connective tissue and endothelial cells (IL-8, MCP-1, etc.). These reinforce those made directly by the mononuclear phagocytes themselves. Circulating leukocytes then attach to the `sticky' endothelium and migrate out into the tissues, presumably in response to the chemokines. These recruited leukocytes are then primed for phagocytosis at an inflammatory site by the combined action of TNF, IL-1, colony-stimulating factors, and chemokines. TNF and IL-1 also cause production of small mediators. They induce cyclooxygenase 2 which generates prostaglandin E2 (or prostacyclin from endothelium), which causes vasodilation and enhances perception of pain. In conjunction with IFN they induce NO synthase: NO contributes to vasodilation. TNF and IL-1 also cause expression of tissue factor and platelet-activating factor, thus locally enhancing clotting mechanisms. IL-6 is a major product of IL-1- or TNF-stimulated cells. It is best known for its systemic action on the liver, causing production of acute phase proteins, an action it shares with oncostatin M and leukemia inhibitory factor (LIF). It is also necessary for promoting the fever induced by TNF and IL-1. Local actions of IL-6 at sites of inflammation are not well characterized: it is an important B cell differentiation factor. Prolonged production of IL-1 and TNF causes connective tissue re-modeling or frank tissue destruction. This is associated with production of various metalloproteinases which break down connective tissue matrix and inhibition of synthesis of new matrix proteins such as proteoglycans and collagen. In a physiological situation, these effects of IL-1 and TNF are probably a prelude to resolution of inflammation by fibrous repair such as is seen in wound healing. The catabolic effects of IL-1 and TNF may be enhanced by the IL-6-type cytokines. IL-1R There are two IL-1 receptors: type I and type II. They are related members of the immunoglobulin superfamily. Type I IL-1R is the signaling receptor and is

295

widely expressed. Type II IL-1R is a related molecule but only has a short cytoplasmic domain (20 amino acids) and has not so far been shown to signal. It is expressed on myeloid cells and may act as a decoy receptor. It is shed upon cell activation and may function as an inhibitor.

TNF superfamily of cytokines

There are a number of TNF-related cytokines which have been molecularly defined in recent years. The first were TNF and TNF (also known as LT), which both react with the TNF receptors (p55 type I and p75 type II). When these receptors were cloned it became apparent that they were related in structure and sequence to nerve growth factor receptor: apart from the latter the TNF/TNFR superfamily are primarily involved in the immune and inflammatory mechanisms. A representation of this growing family is shown in Table 2 (Ware et al., 1998). The TNF/TNFR superfamily molecules are involved in a variety of processes, many of which involve cell activation, growth, and regulation of apoptosis. Many of the TNFR family members can induce apoptosis (e.g. Fas, TNFR, death receptor 3). The former include the protein interaction domain termed the `death domain', but other TNFR family members lacking it, e.g. TNFR p75 (type II) and CD30, can also cause apoptic cell death. Members of the TNF family, e.g. TNF, LT, CD40L, CD27L, 4-1BBL, induce cell activation and growth in the short term. There is a marked overlap in function of many of the proteins in the TNF/ TNFR family, which is explained in large part by sharing of receptors and intracellular signaling pathways. There has been considerable progress in the analysis of TNFR family signaling. There are shared structural aspects of the TNF/TNFR family, which has helped recognize functionally uncharacterized `orphan' members. TNF family members are all type II transmembrane proteins (with the C-terminal on the outside of the cell), with a transmembrane region and a cytoplasmic region, which for TNF is very long. LT is an exception, it is a secreted protein with a typical leader sequence. While most of the remainder are active principally on the cell surface e.g. Fas, CD40, these proteins are shed by enzymes which belong to the ADAMS family (a disintegrin and metalloproteinase). The TNF-converting enzyme (TACE), is now termed ADAMS 17. TNF is active in both surface and shed forms, the latter diffusing more widely. Cell surface TNF preferentially acts on p75 TNFR. The bioactive form of all the TNF family is believed to be the trimer.

Table 2 TNF family ligands Protein Alternative names TNF, cachectin Size (kDa) Secreted Chromosome location Mouse 17 Shed 17 MHC Human 6 MHC Major producers Macrophages, T cells, NK keratinocytes, neutrophils, mast cells T, B, and NK cells T, B, and NK cells Function Reference

TNF

Induces inflammation, activates antigen presentation, upregulates adhesion molecules and chemokines. Has role in rheumatoid arthritis and Crohn's disease Induces inflammation and immunity, can do same things as TNF. Possible role in multiple sclerosis. LT heterotrimer is involved in the development of lymph nodes and spleen. In the absence of LT , there are no peripheral lymph nodes. Mesenteric nodes remain, as do Peyer's patches Fas ligand crosslinks Fas and this often leads to cell death. However, some Fas cells may be activated by FasL. FasL can also act as a receptor CD27L CD30L CD40L is a powerful signal, interacting with CD40 on macrophages, dendritic cells, B cells, endothelium and leads to powerful activation of the immune and inflammatory responses. Lack of CD40L in humans yields the hyper IgM type of immune deficiency Induces activation of Ox40 cells (activated T chiefly), migration into B follicles Involved in costimulation

Pennica et al., 1984; Feldmann et al., 1997; Targan et al., 1997

LT

TNF

25

Yes

17 MHC

6 MHC

Gray et al., 1984

LT

p33; heterotrimers with LT-

33

No

17 MHC

6 MHC

Browning et al., 1993

FasL

Apo1

45

Shed

1q23

T cells, reproductive, lens tissue B cells, thymic stroma, T cells T cells, monocytes T cells, mast cells

Suda et al., 1993

CD27L CD30L CD40L

CD70

50 40

? ? ?

? 4 ?

19p13 9q33 Xq26

Baum et al., 1994; Goodwin et al., 1993a Smith et al., 1993 Graf et al., 1992; Armitage et al., 1992

Gp39

39

Ox40L

34

1q25

T cells, DC, endothelium Lymphoid, stromal lines

Baum et al., 1994

4-1BBL

50

17 Non-MHC

19p13

Goodwin et al., 1993b

TRAIL TWEAK

Apo2

Calc.32.5 18

Yes Yes

? ?

3q26 17p13

Broad Broad

Induces apoptosis of tumors via interacting with its receptors DR3, DR4 Induces IL-8, apoptosis induction, relatively weak induces proliferation endothelium and smooth muscle Induces apoptosis, NF B

Wiley et al., 1995 Chicheportiche, 1997

Apo3L

Apo3, TRAMP

25

17p13

Broad

Marsters, 1998

Modified from Ware et al. (1998) In ``Cytokine Handbook'' (ed A. S. Thomson), pp. 549592. Academic Press, London

298 Marc Feldmann and Jeremy Saklatvala Whereas most TNF family members are homotrimers, LT exists in several forms: secreted homotrimeric LT, and the distinct cell surface heterotrimeric LT, which can exist as LT12 or LT22 1. LT1 2 is the most abundant form on cell surface. The TNFR family has clearly conserved features. They are all type I membrane glycoproteins. The extracellular region is made up of 40 amino acid cysteine-rich domains (six cysteines per domain). There are between three and six of these domains in the extracellular region, usually four. The cytoplasmic regions of the TNFR family share little homology apart from the `death domain', which is a protein aggregation domain in some of these receptors. Despite the lack of homology these receptors interact, after aggregation with a shared family of signaling components, and hence can initiate similar responses. The properties of the TNFR family are illustrated in Table 3. antigen-presenting function in macrophage-derived dendritic cells. GM-CSF is involved in the differentiation of dendritic cells from precursors, either CD34 or monocytes (Stanley, 1992; Metcalf, 1993).

Cytokine inducers of immunity

Macrophages, in common with other antigenpresenting cells (APCs), produce a range of cytokines which have potent effects on the immune system. Major proinflammatory cytokines such as IL-1, TNF, and IL-6 also are proimmune, upregulate IL-2 receptors and activate B cells. There is also another series of molecules produced chiefly by macrophages and other APCs which are important in the activation of the immune response, such as IL-15, IL-12, and IL-18. IL-15 IL-15 is one of the major early activators of T cells and NK cells. This is because functionally IL-15 has a very similar spectrum of activity to IL-2, now understood because as the signal transduction chains of the IL-2R (the  and  chains) are also used by IL-15. However, as the IL-15 chain (unlike the IL-2 chain) is constitutively expressed, this permits IL-15 to be involved in the early activation of T and NK cells, prior to the CD25 component of the highaffinity upregulation of the IL-2 receptor. In view of its powerful effects on the immune system, IL-15 is produced in small amounts, and the presence of 10 potential AUG transcriptional start sites in the IL-15 promoter is probably of major importance in limiting the rate of protein production. Once produced, the properties of IL-15 would be similar to those of IL-2, namely growth and activation of T lymphocytes, B lymphocytes, macrophage activation, NK activation, etc. (Tagaya et al., 1996). IL-12 IL-12 is structurally unusual, as it is a heterodimeric cytokine. The p40 chain is produced relatively abundantly, but only when coupled to the p35 chain, which is very sparingly produced, is the bioactive form (p70) generated. IL-12 acts on T cells and NK cells to activate them. On T cells it activates na ve CD4 `TH0' cells towards the CD4 `TH1' cells which have a proinflammatory phenotype. These are T cells which produce IL-2 and IFN but not IL-4 and help downregulate the CD4 TH2 `allergic' phenotype (cells which produce IL-4 and IL-5). IL-12

IL-6
IL-6 has some undeniably proinflammatory features, for example it induces fever. However, it also has some anti-inflammatory features, such as the capacity to partly downregulate TNF production. IL-6 also has major effects on the immune system, activating B cells to produce immunoglobulin, and T cells to upregulate receptors for IL-2. The properties of IL-6 are discussed in detail in the chapters on the IL-6 Ligand and Receptor Family and IL-6 (Kishimoto et al., 1992).

Colony-stimulating factors are important inducers of inflammation and haemopoiesis

While colony-stimulating factors such as GM-CSF and M-CSF were discovered initially as haemopoietic growth factors, they are also proinflammatory molecules. M-CSF promotes the survival of monocytes and macrophages which has proinflammatory consequences, and it activates macrophages (Stanley, 1992). M-CSF promotes macrophage differentiation, one consequence of which is that the ratio of proinflammatory to anti-inflammatory cytokines produced is altered, for example producing less IL-1 and more IL-1 receptor antagonist. GM-CSF is markedly proinflammatory and leads to a marked adjuvant effect. It is able to augment the production of IL-1 and TNF, as well as itself, it augments the expression of HLA class II antigens, and augments

Table 3 TNF receptor family Receptor Alternative names TNFR55, R1 TNFR75, R2 TNFrrp Fas, Apo1 ILA(hu) ACT35(hu) Tp55 Ki-1 Bp50, p50 p75, NGFR WSL-1, DR3, LARD, APO-3 ATAR, TR2 Ligands Size (kDa) Soluble forms Shed Shed ? Alternate splice Alternate splice ? Shed ? Shed Shed Spliced Chromosome location Mouse 6 4 6 19 4 4 6 4 2 11 Human 12p13 1p36 12p13 10 1p36 1p36 12p13 1p36 20q11q13 17q2122 1p36.2 Tissue expression Broad Hematopoietic, broad Broad Lymphocytes, broad T cells, broad CD4+ T cells Resting T cells Hematopoietic, Hodgkin's lymphoma B and T cells, endothelium, DC, macrophages Nervous system Broad Negative selection thymus Powerful activation Function References

CD120 CD120 LT R CD95 4-1BB Ox40 CD27 CD30 CD40 NTR TRAMP

TNF, LT, LT2 1 TNF, LT, LT2 1 LT1 2 FasL 4-1BBL Ox40L CD70, CD27L CD30L CD40L, gp39, TBAM, TRAP NGF, neurotropins ?

5560 7580 61 43 33 48 5055 dimer 120 4347 75

Inflammation, apoptosis Immunity, inflammation Lymphogenesis Apoptosis Costimulation On activated T cells only

Schall et al., 1990; Loetscher et al., 1990; Gray et al., 1990 Smith et al., 1990 Rennert et al., 1998 Itoh et al., 1991 Vinay and Kwon, 1998 Mallett et al., 1990 Kobata et al., 1994; Hintzen et al., 1995 Amakawa et al., 1996 Grewel and Flavel, 1998 Rabizadeh et al., 1993 Marsters et al., 1996; Bodmer et al., 1997; Screaton et al., 1997; Schneider et al., 1999 Harrop et al., 1998; Mauri et al., 1998 Brojatsch et al., 1996

HVEM CAR-1

? ?

42 ?

? ?

1p36

Lymphocytes, broad Chicken receptor for avian leukosis sarcoma virus, induces apoptosis

OPG

OPGL, RANKL

55 mono

Secreted

8q2324

Broad

Regulates bone development

Takahashi et al., 1999; Simonet et al., 1997

Table 3 (Continued ) Receptor Alternative names Ligands Size (kDa) Soluble forms ? ? ? ? Chromosome location Mouse ? ? ? ? Human ? ? ? ? Tissue expression T lymphocytes T cells, broad Broad Broad, normal tissue Function References

GITR DR4 DR5 TRID DcR1

? TRAIL TRAIL TRAIL

23 ? ? ?

Inhibits apoptosis in T cells Apoptosis Apoptosis Apoptosis

Nocentini et al., 1997 Zamai et al., 1998 Sheridan et al., 1997 Pan et al., 1997

NGF, nerve growth factor; TNFrrp, TNF receptor-related protein.

Modified from Ware et al. (1998) In ``Cytokine Handbook'' (ed A. S. Thomson), pp. 549592, Academic Press, London

Proinflammatory Cytokines is a very potent inducer of IFN , but its capacity to generate TH1 cells is not solely dependent in this property. IL-12 has strong adjuvant activity and is produced by APC most abundantly by dendritic cells, macrophages, and B lymphocytes (Trinchieri, 1995). IL-18 IL-18 was first described as `interferon  -inducing factor', but is now known to act as a cofactor with IL12 in the generation of TH1 type cells which produced IFN . Structurally, it has been found to be conformationally related to IL-1, and its receptor uses a similar signal transduction pathway. TH1 cells have receptors for IL-18, but not for IL-1, and the TH2 cells have receptors for IL-1 but not for IL-18. The strong proinflammatory effects of IL-12 are much diminished in the absence of IL-18.

301

and are kept in check by a series of `killer inhibitory' receptors of which there are two families. Cytokines such as IL-15, IFN, IFN , and IL-2 also activate NK cells (Moretta and Mingari, 1999).

EOSINOPHILS
Eosinophils are very important in the immune response to parasites and in allergic reactions in the airways, such as asthma. The generation of eosinophils is highly dependent on the cytokines, especially IL-5 but also IL-3 and GM-CSF and their recruitment to tissues is highly dependent on the CCR3 receptor, which binds eotaxin, eotaxin 2, RANTES, MCP-2, MCP-3, and MCP-4. In the tissues, activation depends on a variety of signals, which include cytokines such as IL-5, GMCSF, IL-3, TNF, IFN , immune complexes (receptors for IgA, E, G), chemokines (see above), integrins, lipid mediators, e.g. PAF, leukotriene B4, and complement components. Upon activation, eosinophils release a variety of mediators. Most abundant is a basic protein `major basic protein' which is a cytotoxin. Enzymes such as peroxidase are also abundant. Cytokines released include TNF, IL-6, IL-1, IL-3, IL-5, IL-8, MIP1, TGF, and TGF (Rosenberg, 1999; Moqbel et al., 1994).

GRANULOCYTES AND THEIR PRODUCTS

Granulocytes were once thought not to produce cytokines. The early reports of cytokines released by granulocytes were attributed to the small fraction of contaminating macrophages. Gradually, with improved methods of purifying and studying granulocytes, it became accepted that granulocytes do produce cytokines. While producing much less per cell, typically about 1/10 that of macrophages, since granulocytes are 510 fold more abundant than macrophages in the blood and especially in early inflammatory sites, it means that they are major sources of cytokines. As they traffic to sites of inflammation more rapidly than macrophages, their cytokines are of major importance in the rapid mobilization of host defenses, and in the induction and recruitment of other cells into sites of inflammation (Bainton, 1999). Other products of granulocytes such as oxygen and nitrogen radicals, abundant peptides such as defensins have major functions in host defense, and can be involved in inducing cytokines from neighboring cells.

MAST CELLS AND BASOPHILS

There are two basic types of mast cells resident in tissues, with some variation in properties. Basophils are in the blood, and are closely selected to mast cells. Rodent and human mast cells vary in their characteristics. Human mast cells are divided into those with tryptase only and those with both tryptase and chymase. The former are T cell dependent, found in lungs, nasal mucosa and mucosa of intestine inhibited by sodium cromoglycate. The latter are T cell independent, found in skin, tonsils, and intestinal submucosa, not inhibited by sodium cromoglycate. Mast cells are activated by cytokines, including IFN , TNF, IL-1, IL-3, GM-CSF, SCF, and immune complexes especially those of IgE. The activation and degranulation of mast cells is a prominent feature of acute inflammatory and especially acute allergic responses. This leads to the release of mediators such as bradykinin, serotonin, histamine, prostaglandins, leukotrienes, cytokines, and may lead to the potentially fatal symptoms of anaphylaxis.

NK CELLS
These cells are closely related to T lymphocytes, and can produce the same repertoire of cytokines, as well as the cytolytic proteins, granzymes, and perforin. They are activated by interaction with a different receptor system, which has been recently elucidated

302 Marc Feldmann and Jeremy Saklatvala Mast cells produce an unusually large spectrum of cytokines, including many which were considered to be the province of T cells such as IL-2, IL-4, IL-3, IFN , GM-CSF, and IL-5. They also produce and store TNF, make IL-1, IL-6, chemokines such as IL-8, MIP-1, MIP-1 , and MCP-1. Mast cells and their physiology were recently reviewed by Metcalf et al. (1997). neutrophil-activating peptide 2 (NAP-2), and RANTES (Endreson and Forre, 1992; Power et al., 1995; Marcus, 1999). They also have membranebound IL-1, which may be important in activation of the endothelium (Hawrylowicz et al., 1991).

FIBROBLASTS
Fibroblasts, like all other cells, respond to a wide variety of cytokines and can make a number of cytokines. Fibroblasts respond to IL-1, TNF, IL-4, IFN/, IFN , PDGF, FGFs, TGF, EGF, etc. Fibroblasts produce IL-6. They also produce chemokines such as IL-8, MCP-1, MCP-2, MCP-4, KC, MIP-1, RANTES, GM-CSF, M-CSF, G-CSF, IL1, IL-11, VEGF, PDGF-AA, TGF, TGF , and FGF-7 (reviewed by Postlethwaite and Kang, 1999).

ENDOTHELIAL CELLS
Endothelial cells are a heterogeneous collection of cells, and it is likely that the properties of venous, arterial, microvascular (capillary) as well as lymphatic endothelium will differ in their cytokine production profile, as they do for other parameters. The production of endothelial cytokines is likely to be very important in coordinating the recruitment of cells from the blood. The major cytokines to which endothelial cells respond to include VEGF, PDGF, FGF, TNF, IL-1, IL-4, IL-6, and IFN . The production of cytokines from endothelium has chiefly been studied using human vascular endothelial cells (abbreviated commonly as HUVECs). These cells are fetal, and it is unlikely that they reflect fully the properties of adult cells and various types of endothelium. HUVECs make abundant IL-6, IL-8 and other chemokines, such as MCP-1, RANTES, GRO1. They also make IL-1, IL-5, IL-11, IL-15, GCSF, GM-CSF, and M-CSF. There is no clear evidence for HUVEC production of TNF protein, although mRNA has been detected (Krishnaswamy et al., 1999; Silverstein, 1999). The situation in microvessels in inflammatory sites such as rheumatoid synovium is probably different. There are several reports of immunostaining for TNF, and for VEGF, cytokines not made by HUVECs. The cytokine production by endothelial cells is likely to be important in the context of a wide variety of diseases, including atherosclerosis, graft rejection, vasculitis, sepsis, etc.

KERATINOCYTES
Keratinocytes are unusual in that they store a number of cytokines, which then are sloughed together with the epidermal cells. It has been speculated that this process is an important form of secretion of cytokines from the body. Keratinocytes store IL-1, IL-1 chiefly, less IL-1, IL-1 receptor antagonist (multiple isoforms), IL-3, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, TGF, TGF , bFGF, PDGF, VEGF, G-CSF, MCSF, GM-CSF, TNF, and other chemokines such as MCP-1,  IP-10. Cytokine disregulation in the epidermis may be involved in various diseases such as psoriasis, Kaposi's sarcoma, and pemphigus (reviewed by Feliciani et al., 1996).

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