Interleukin

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Interleukins are a group of cytokines (secreted proteins/signaling molecules) that were first
seen to be expressed by white blood cells (leukocytes). The term interleukin derives from
(inter-) "as a means of communication", and (-leukin) "deriving from the fact that many of
these proteins are produced by leukocytes and act on leukocytes". The name is something of
a relic though (the term was coined by Dr. Paetkau, University of Victoria); it has since been
found that interleukins are produced by a wide variety of body cells. The function of the
immune system depends in a large part on interleukins, and rare deficiencies of a number of
them have been described, all featuring autoimmune diseases or immune deficiency. The
majority of interleukins are synthesized by helper CD4+ T lymphocytes, as well as through
monocytes, macrophages, and endothelial cells. They promote the development and
differentiation of T, B, and hematopoietic cells.

Common families of interleukins

[edit] Interleukin-1

Interleukin-1
Identifiers
Symbol Interleukin_1
Pfam PF00340
InterPro IPR000975
SMART SM00125
PROSITE PDOC00226
[show]Available PDB structures:

Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that
participate in the regulation of immune responses, inflammatory reactions, and
hematopoiesis.[1]. Two types of IL-1 receptor, each with three extracellular immunoglobulin
(Ig)-like domains, limited sequence similarity (28%) and different pharmacological
characteristics have been cloned from mouse and human cell lines: these have been termed
type I and type II receptors[2] The receptors both exist in transmembrane (TM) and soluble
forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of
the extracellular portion of the membrane receptors.

Both IL-1 receptors (CD121a/IL1R1, CD121b/IL1R2 ) appear to be well conserved in

evolution, and map to the same chromosomal location.[3] The receptors can both bind all three
forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1RA).

The crystal structures of IL1A and IL1B[4] have been solved, showing them to share the same
12-stranded beta-sheet structure as both the heparin binding growth factors and the Kunitz-
type soybean trypsin inhibitors.[5] The beta-sheets are arranged in 3 similar lobes around a
central axis, 6 strands forming an anti-parallel beta-barrel. Several regions, especially the
loop between strands 4 and 5, have been implicated in receptor binding.

[edit] Interleukin-2

Interleukin-2
Identifiers
Symbol Interleukin-2
Pfam PF00715
InterPro IPR000779
SMART SM00189
PROSITE PDOC00349
[show]Available PDB structures:

T-Lymphocytes regulate the growth and differentiation of certain lymphopoietic and

haemopoietic cells through the release of various secreted protein factors.[6] These factors,
which include interleukin-2 (IL2), are secreted by lectin- or antigen-stimulated T-cells, and
have various physiological effects. IL2 is a lymphokine that induces the proliferation of
responsive T-cells. In addition, it acts on some B-cells, via receptor-specific binding,[7] as a
growth factor and antibody production stimulant.[8] The protein is secreted as a single
glycosylated polypeptide, and cleavage of a signal sequence is required for its activity.[7]
Solution NMR suggests that the structure of IL2 comprises a bundle of 4 helices (termed A-
D), flanked by 2 shorter helices and several poorly-defined loops. Residues in helix A, and in
the loop region between helices A and B, are important for receptor binding. Secondary
structure analysis has suggested similarity to IL4 and granulocyte-macrophage colony
stimulating factor (GMCSF).[8]

[edit] Interleukin-3

Interleukin-3
Identifiers
Symbol Interleukin_3
Pfam PF02059
InterPro IPR002183
[show]Available PDB structures:

Interleukin-3 (IL3) is a cytokine that regulates blood-cell production by controlling the

production, differentiation and function of granulocytes and macrophages[9][10]. The protein,
which exists in vivo as a monomer, is produced in activated T-cells and mast cells[9][10], and is
activated by the cleavage of an N-terminal signal sequence[10].

IL3 is produced by T-lymphocytes and T-lymphomas only after stimulation with antigens,
mitogens, or chemical activators such as phorbol esters. However, IL3 is constitutively
expressed in the myelomonocytic leukaemia cell line WEHI-3B.[10] It is thought that the
genetic change of the cell line to constitutive production of IL3 is the key event in
development of this leukaemia.[10]

[edit] Interleukin-5

Interleukin-5
Identifiers
Symbol Interleukin_5
Pfam PF02025
InterPro IPR000186
[show]Available PDB structures:

Interleukin-5 (IL5), also known as eosinophil differentiation factor (EDF), is a lineage-

specific cytokine for eosinophilpoiesis.[11][12] It regulates eosinophil growth and activation[11],
and thus plays an important role in diseases associated with increased levels of eosinophils,
including asthma.[12] IL5 has a similar overall fold to other cytokines (e.g., IL2, IL4 and
GCSF)[12], but while these exist as monomeric structures, IL5 is a homodimer. The fold
contains an anti-parallel 4-alpha-helix bundle with a left handed twist, connected by a 2-
stranded anti-parallel beta-sheet.[12][13] The monomers are held together by 2 interchain
disulphide bonds.[13]

[edit] Interleukin-6

Interleukin-6/G-CSF/MGF
Identifiers
Symbol IL6_MGF_GCSF
Pfam PF00489
InterPro IPR003573
SMART SM00126
PROSITE PDOC00227
[show]Available PDB structures:

Interleukin-6 (IL6), also referred to as B-cell stimulatory factor-2 (BSF-2) and interferon
beta-2, is a cytokine involved in a wide variety of biological functions.[14] It plays an essential
role in the final differentiation of B-cells into IG-secreting cells, as well as inducing
myeloma/plasmacytoma growth, nerve cell differentiation, and, in hepatocytes, acute-phase
reactants.[14][15]

A number of other cytokines may be grouped with IL6 on the basis of sequence similarity.[14]
[15][16]
These include granulocyte colony-stimulating factor (GCSF) and myelomonocytic
growth factor (MGF). GCSF acts in hematopoiesis by affecting the production,
differentiation, and function of 2 related white cell groups in the blood.[16] MGF also acts in
hematopoiesis, stimulating proliferation and colony formation of normal and transformed
avian cells of the myeloid lineage.

Cytokines of the IL6/GCSF/MGF family are glycoproteins of about 170 to 180 amino acid
residues that contains four conserved cysteine residues involved in two disulphide bonds:[16].
They have a compact, globular fold (similar to other interleukins), stabilised by the 2
disulphide bonds. One half of the structure is dominated by a 4-alpha-helix bundle with a left-
handed twist;[17] the helices are anti-parallel, with 2 overhand connections, which fall into a 2-
stranded anti-parallel beta-sheet. The fourth alpha-helix is important to the biological activity
of the molecule.[15]

[edit] Interleukins 7 and 9

Interleukin-7/interleukin-9
Identifiers
Symbol Interleukin_7_9
Pfam PF01415
InterPro IPR000226
PROSITE PDOC00228

Interleukin-7 (IL-7)[18] is a cytokine that serves as a growth factor for early lymphoid cells of
both B- and T-cell lineages. Interleukin-9 (IL-9)[19] is a cytokine that supports IL-2
independent and IL-4 independent growth of helper T-cells. Interleukin-7 and -9 seems to be
evolutionary related.[20]

[edit] Interleukin-10

Interleukin-10
Identifiers
Symbol Interleukin_10
Pfam PF00726
InterPro IPR000098
SMART SM00188
PROSITE PDOC00450
[show]Available PDB structures:

Interleukin-10 (IL-10) is a protein that inhibits the synthesis of a number of cytokines,

including IFN-gamma, IL-2, IL-3, TNF, and GM-CSF produced by activated macrophages
and by helper T cells. In structure, IL-10 is a protein of about 160 amino acids that contains
four conserved cysteines involved in disulphide bonds.[21] IL-10 is highly similar to the
Human herpesvirus 4 (Epstein-Barr virus) BCRF1 protein, which inhibits the synthesis of
gamma-interferon and to Equid herpesvirus 2 (Equine herpesvirus 2) protein E7. It is also
similar, but to a lesser degree, with human protein mda-7.[22] a protein that has
antiproliferative properties in human melanoma cells. Mda-7 contains only two of the four
cysteines of IL-10.

[edit] Interleukin-11

Interleukin 11
Identifiers
Symbol IL11
Pfam PF07400
InterPro IPR010873

Interleukin-11 (IL-11) is a secreted protein that stimulates megakaryocytopoiesis, resulting in

increased production of platelets, as well as activating osteoclasts, inhibiting epithelial cell
proliferation and apoptosis, and inhibiting macrophage mediator production. These functions
may be particularly important in mediating the hematopoietic, osseous and mucosal
protective effects of interleukin 11.[23] Family members seem to be restricted to mammals.

[edit] Interleukin 12

Interleukin-12 alpha subunit

Identifiers
Symbol IL12
Pfam PF03039
InterPro IPR004281
[show]Available PDB structures:

Interleukin-12 (IL-12) is a disulphide-bonded heterodimer consisting of a 35kDa alpha

subunit and a 40kDa beta subunit. It is involved in the stimulation and maintenance of Th1
cellular immune responses, including the normal host defence against various intracellular
pathogens, such as Leishmania, Toxoplasma, Measles virus, and Human immunodeficiency
virus 1 (HIV). IL-12 also has an important role in pathological Th1 responses, such as in
inflammatory bowel disease and multiple sclerosis. Suppression of IL-12 activity in such
diseases may have therapeutic benefit. On the other hand, administration of recombinant IL-
12 may have therapeutic benefit in conditions associated with pathological Th2 responses.[24]
[25]

[edit] Interleukin-13

Interleukin-13
Identifiers
Symbol Interleukin_13
Pfam PF03487
InterPro IPR003634
 [show]Available PDB structures:

Interleukin-13 (IL-13) is a pleiotropic cytokine that may be important in the regulation of the
inflammatory and immune responses[26]. It inhibits inflammatory cytokine production and
synergises with IL-2 in regulating interferon-gamma synthesis. The sequences of IL-4 and
IL-13 are distantly related.

[edit] Interleukin-15

Interleukin 15
Identifiers
Symbol Interleukin_15
Pfam PF02372
InterPro IPR003443

Interleukin-15 (IL-15) is a cytokine that possesses a variety of biological functions, including

stimulation and maintenance of cellular immune responses.[27] IL-15 stimulates the
proliferation of T-lymphocytes, which requires interaction of IL-15 with components of IL-
2R, including IL-2R beta and probably IL-2R gamma, but not IL-2R alpha.

[edit] Interleukin-17

Interleukin-17
Identifiers
Symbol IL17
Pfam PF06083
InterPro IPR010345
[show]Available PDB structures:

Interleukin-17 (IL-17) is a potent proinflammatory cytokine produced by activated memory T

cells.[28] The IL-17 family is thought to represent a distinct signalling system that appears to
have been highly conserved across vertebrate evolution.[28]

[edit] List of human interleukins

A list of interleukins:

Name Source [29] Target receptors[29][30] Target cells[29] Function[29]

IL-1 macrophages, B CD121a/IL1R1, T helper cells co-stimulation [31]
cells, monocytes CD121b/IL1R2 maturation &
[31]
, dendritic B cells
proliferation [31]
cells [31] NK cells activation[31]
macrophages, inflammation[31], small
endothelium, other amounts induce acute
 phase reaction, large
amounts induce fever
stimulates growth and
differentiation of T cell
response. Can be used in
activated[31] T cells
immunotherapy to treat
CD25/IL2RA, and B cells, NK
cancer or suppressed for
IL-2 Th1-cells CD122/IL2RB, cells,
transplant patients. Has
CD132/IL2RG macrophages,
also been used in clinical
oligodendrocytes
trials (ESPIRIT. Stalwart)
to raise CD4 counts in
HIV positive patients.
differentiation and
activated T
proliferation of myeloid
helper cells[31], hematopoietic
progenitor cells [31] to e.g.
mast cells, NK CD123/IL3RA, stem cells
IL-3 erythrocytes,
cells, CD131/IL3RB
granulocytes
endothelium,
growth and histamine
eosinophils mast cells
release[31]
proliferation and
Th2 cells, just differentiation, IgG1 and
activated naive activated B cells IgE synthesis[31].
CD4+ cell, CD124/IL4R, Important role in allergic
IL-4
memory CD4+ CD132/IL2RG response (IgE)
cells, mast cells,
T cells proliferation[31]
macrophages
endothelium
Th2 cells, mast eosinophils production
CD125/IL5RA,
IL-5 cells, differentiation, IgA
CD131/IL3RB B cells
eosinophils production
differentiation into
activated B cells
plasma cells
plasma cells antibody secretion
macrophages,
hematopoietic
Th2 cells, B CD126/IL6RA, differentiation
IL-6 stem cells
cells, astrocytes, CD130/IR6RB
endothelium induces acute phase
reaction, hematopoiesis,
T cells, others
differentiation,
inflammation
differentiation and
proliferation of lymphoid
Bone marrow progenitor cells, involved
pre/pro-B cell,
stromal cells CD127/IL7RA, in B, T, and NK cell
IL-7 pre/pro-T cell, NK
and thymus CD132/IL2RG survival, development,
cells
stromal cells and homeostasis,
↑proinflammatory
cytokines
IL-8 macrophages, CXCR1/IL8RA, neutrophils, Neutrophil chemotaxis
lymphocytes, CXCR2/IL8RB/CD128 basophils,
 epithelial cells,
lymphocytes
endothelial cells
Th2 cells,
specifically by Potentiates IgM, IgG,
IL-9 CD129/IL9R T cells, B cells
CD4+ helper IgE, stimulates mast cells
cells
macrophages cytokine production[31]
monocytes, Th2 B cells activation [31]
cells, CD8+ T mast cells
CD210/IL10RA,
IL-10 cells, mast cells, inhibits Th1 cytokine
CDW210B/IL10RB
macrophages, B Th1 cells production (IFN-γ, TNF-
cell subset β, IL-2)
Th2 cells Stimulation
acute phase protein
bone marrow bone marrow
IL-11 IL11RA production, osteoclast
stroma stroma
formation
differentiation into
dendritic cells, activated [31] T Cytotoxic T cells with
CD212/IL12RB1,
IL-12 B cells, T cells, cells, IL-2[31], ↑ IFN-γ, TNF-α,
IR12RB2
macrophages ↓ IL-10
NK cells ↑ IFN-γ, TNF-α
Stimulates growth and
differentiation of B cells
(IgE), inhibits TH1-cells
activated Th2
TH2-cells, B cells, and the production of
IL-13 cells, mast cells, IL13R
macrophages macrophage
NK cells
inflammatory cytokines
(e.g. IL-1, IL-6), ↓ IL-8,
IL-10, IL-12
T cells and
controls the growth and
certain
IL-14 activated B cells proliferation of B cells,
malignant B
inhibits Ig secretion
cells
mononuclear
phagocytes (and
some other
cells), especially T cells, activated Induces production of
IL-15 IL15RA
macrophages B cells Natural killer cells
following
infection by
virus(es)
lymphocytes,
epithelial cells, CD4+ T cells (Th-
IL-16 CD4 CD4+ chemoattractant
eosinophils, cells)
CD8+ T cells
osteoclastogenesis,
T helper 17 cells CDw217/IL17RA, epithelium,
IL-17 angiogenesis, ↑
(Th17) IL17RB endothelium, other
inflammatory cytokines
 Th1 cells, NK Induces production of
IL-18 macrophages CDw218a/IL18R1
cells IFNγ, ↑ NK cell activity
IL-19 - IL20R -
regulates proliferation
IL-20 - IL20R and differentiation of
keratinocytes
costimulates activation
and proliferation of
CD8+ T cells, augment
NK cytotoxicity,
activated T
All lymphocytes, augments CD40-driven B
IL-21 helper cells, IL21R
dendritic cells cell proliferation,
NKT cells
differentiation and
isotype switching,
promotes differentiation
of Th17 cells
Activates STAT1 and
STAT3 and increases
production of acute phase
proteins such as serum
IL-22 - IL22R
amyloid A, Alpha 1-
antichymotrypsin and
haptoglobin in hepatoma
cell lines
Increases angiogenesis
IL-23 - IL23R but reduces CD8 T-cell
infiltration
Plays important roles in
tumor suppression,
IL-24 - IL20R wound healing and
psoriasis by influencing
cell survival.
Induces the production
IL-4, IL-5 and IL-13,
IL-25 - LY6E
which stimulate
eosinophil expansion
Enhances secretion of IL-
10 and IL-8 and cell
IL-26 - IL20R1
surface expression of
CD54 on epithelial cells
Regulates the activity of
IL-27 - IL27RA B lymphocyte and T
lymphocytes
Plays a role in immune
IL-28 - IL28R
defense against viruses
Plays a role in host
IL-29 -
defenses against microbes
IL-30 - Forms one chain of IL-27
IL-31 - IL31RA May play a role in
 inflammation of the skin
Induces monocytes and
IL-32 - macrophages to secrete
TNF-α, IL-8 and CXCL2
Induces helper T cells to
IL-33 -
produce type 2 cytokine
regulatory T Suppression of T helper
IL-35
cells cell activation