Interleukin

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

Interleukin-1

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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.. 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 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. 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 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. 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.

Interleukin-2

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T-Lymphocytes regulate the growth and differentiation of certain lymphopoietic and haemopoietic cells through the release of various secreted protein factors. 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, as a growth factor and antibody production stimulant. The protein is secreted as a single glycosylated polypeptide, and cleavage of a signal sequence is required for its activity.. The protein, which exists in vivo as a monomer, is produced in activated T-cells and mast cells.

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.

Interleukin-5

}} Interleukin-5 (IL5), also known as eosinophil differentiation factor (EDF), is a lineage-specific cytokine for eosinophilpoiesis. It regulates eosinophil growth and activation, 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. The monomers are held together by 2 interchain disulphide bonds. 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.

A number of other cytokines may be grouped with IL6 on the basis of sequence similarity. 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.. 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 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.

Interleukins 7 and 9

Interleukin-7 (IL-7) is a cytokine that serves as a growth factor for early lymphoid cells of both B- and T-cell lineages. Interleukin-9 (IL-9) 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.

Interleukin-10

}} 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. Structurally, IL-10 is a protein of about 160 amino acids that contains four conserved cysteines involved in disulphide bonds. 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. a protein which has antiproliferative properties in human melanoma cells. Mda-7 only contains two of the four cysteines of IL-10.

Interleukin-11

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. Family members seem to be restricted to mammals.

Interleukin 12

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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.

Interleukin-13

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Interleukin-13 (IL-13) is a pleiotropic cytokine which may be important in the regulation of the inflammatory and immune responses. 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.

Interleukin-15

Interleukin-15 (IL-15) is a cytokine that possesses a variety of biological functions, including stimulation and maintenance of cellular immune responses. 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.

Interleukin-17

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

References

External links

Cytokines & Cells Online Pathfinder Encyclopedia

HGNC Gene Family Nomenclature: Interleukin and Interleukin Receptor Gene Symbols

Interleukin Antibody Review

Category:Immune system Category:Cytokines Category:Immunology