Interleukin

interleukins are a group of cytokines (secreted proteins and signal molecules) that were first seen to be expressed by white blood cells (leukocytes).[1]

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 and B lymphocytes, and hematopoietic cells.

Interleukin receptors on astrocytes in the hippocampus are also known to be involved in the development of spatial memories in mice.[2]

History and name

The name "interleukin" was chosen in 1979, to replace the various different names used by different research groups to designate interleukin 1 (lymphocyte activating factor, mitogenic protein, T-cell replacing factor III, B-cell activating factor, B-cell differentiation factor, and "Heidikine") and interleukin 2 (TSF, etc.). This decision was taken during the Second International Lymphokine Workshop in Switzerland (27-31 May 1979 in Ermatingen, 'near' Interlaken).[3][4][5]

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 Vern Paetkau, University of Victoria) it has since been found that interleukins are produced by a wide variety of body cells.

Some interleukins are classified as lymphokines, lymphocyte-produced cytokines that mediate immune responses.

Common families of interleukins

Interleukin 1

Main article: Interleukin 1
Interleukin 1 / 18

Crystallographic structure of human interleukin 1B.[6]
Identifiers
Symbol IL1
Pfam PF00340
InterPro IPR000975
SMART SM00125
PROSITE PDOC00226
SCOP 1i1b
SUPERFAMILY 1i1b

Interleukin 1 alpha and interleukin 1 beta (IL1 alpha and IL1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis.[7] 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.[8] 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.[9] The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1 receptor antagonist).

The crystal structures of IL1A and IL1B[10] 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.[11] 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.

Molecular cloning of the Interleukin 1 Beta converting enzyme is generated by the proteolytic cleavage of an inactive precursor molecule. A complementary DNA encoding protease that carries out this cleavage has been cloned. Recombinant expression enables cells to process precursor Interleukin 1 Beta to the mature form of the enzyme.

Interleukin 1 also plays a role in the Central Nervous System. Research indicates that mice with a genetic deletion of the type I IL-1 receptor display markedly impaired hippocampal-dependent memory functioning and Long-term potentiation, although memories that do not depend on the integrity of the hippocampus seem to be spared.[12][13] However, when mice with this genetic deletion have wild-type neural precursor cells injected into their hippocampus and these cells are allowed to mature into astrocytes containing the interleukin-1 receptors, the mice exhibit normal hippocampal-dependent memory function, and partial restoration of long-term potentiation.[12]

Interleukin 2

Main article: Interleukin 2
Interleukin 2
Identifiers
Symbol Interleukin-2
Pfam PF00715
InterPro IPR000779
SMART SM00189
PROSITE PDOC00349

T lymphocytes regulate the growth and differentiation of T cells and certain B cells through the release of secreted protein factors.[14] 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,[15] as a growth factor and antibody production stimulant.[16] The protein is secreted as a single glycosylated polypeptide, and cleavage of a signal sequence is required for its activity.[15] 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).[16]

Interleukin 3

Main article: Interleukin 3
Interleukin 3
Identifiers
Symbol Interleukin_3
Pfam PF02059
InterPro IPR002183

Interleukin 3 (IL3) is a cytokine that regulates hematopoiesis by controlling the production, differentiation and function of granulocytes and macrophages.[17][18] The protein, which exists in vivo as a monomer, is produced in activated T cells and mast cells,[17][18] and is activated by the cleavage of an N-terminal signal sequence.[18]

IL3 is produced by T lymphocytes and T-cell 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.[18] 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.[18]

Interleukin 4

Main article: Interleukin 4
Interleukin 4
Identifiers
Symbol Interleukin_4
Pfam PF02059
InterPro IPR002183

Interleukin 4 (IL4) is produced by CD4+ T cells specialized in providing help to B cells to proliferate and to undergo class switch recombination and somatic hypermutation. Th2 cells, through production of IL-4, have an important function in B-cell responses that involve class switch recombination to the IgG1 and IgE isotypes.

Interleukin 5

Main article: Interleukin 5
Interleukin 5
Identifiers
Symbol Interleukin_5
Pfam PF02025
InterPro IPR000186

Interleukin 5 (IL5), also known as eosinophil differentiation factor (EDF), is a lineage-specific cytokine for eosinophilpoiesis.[19][20] It regulates eosinophil growth and activation,[19] and thus plays an important role in diseases associated with increased levels of eosinophils, including asthma.[20] IL5 has a similar overall fold to other cytokines (e.g., IL2, IL4 and GCSF),[20] 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.[20][21] The monomers are held together by 2 interchain disulphide bonds.[21]

Interleukin 6

Main article: Interleukin 6
Interleukin 6/G-CSF/MGF
Identifiers
Symbol IL6_MGF_GCSF
Pfam PF00489
InterPro IPR003573
SMART SM00126
PROSITE PDOC00227

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.[22] It plays an essential role in the final differentiation of B cells into immunoglobulin-secreting cells, as well as inducing myeloma/plasmacytoma growth, nerve cell differentiation, and, in hepatocytes, acute-phase reactants.[22][23]

A number of other cytokines may be grouped with IL6 on the basis of sequence similarity.[22][23][24] 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.[24] 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 contain four conserved cysteine residues involved in two disulphide bonds.[24] They have a compact, globular fold (similar to other interleukins), stabilised by the two disulphide bonds. One half of the structure is dominated by a 4-alpha-helix bundle with a left-handed twist;[25] the helices are anti-parallel, with two overhand connections, which fall into a double-stranded anti-parallel beta-sheet. The fourth alpha-helix is important to the biological activity of the molecule.[23]

Interleukins 7 and 9

Main articles: Interleukin 7 and Interleukin 9
Interleukin 7/interleukin 9
Identifiers
Symbol Interleukin_7_9
Pfam PF01415
InterPro IPR000226
PROSITE PDOC00228

Interleukin 7 (IL-7)[26] is a cytokine that serves as a growth factor for early lymphoid cells of both B- and T-cell lineages. Interleukin 9 (IL-9)[27] is a cytokine that supports IL-2 independent and IL-4 independent growth of helper T cells. Interleukin 7 and 9 seem to be evolutionary related.[28]

Interleukin 8

Main article: Interleukin 8

Interleukin 10

Main article: Interleukin 10
Interleukin 10
Identifiers
Symbol Interleukin_10
Pfam PF00726
InterPro IPR000098
SMART SM00188
PROSITE PDOC00450

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.[29] 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.[30] a protein that has antiproliferative properties in human melanoma cells. Mda-7 contains only two of the four cysteines of IL-10.

Interleukin 11

Main article: 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.[31]

Interleukin 12

Main article: Interleukin 12
Interleukin 12 alpha subunit
Identifiers
Symbol IL12
Pfam PF03039
InterPro IPR004281

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 enhancing the cytotoxic function of NK cells[32][33] and 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.[34][35]

Interleukin 13

Main article: Interleukin 13
Interleukin 13
Identifiers
Symbol Interleukin_13
Pfam PF03487
InterPro IPR003634

Interleukin 13 (IL-13) is a pleiotropic cytokine that may be important in the regulation of the inflammatory and immune responses.[36] 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.[37]

Interleukin 15

Main article: 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.[38] 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

Main article: Interleukin 17
Interleukin 17
Identifiers
Symbol IL17
Pfam PF06083
InterPro IPR010345

Interleukin 17 (IL-17) is a potent proinflammatory cytokine produced by activated memory T cells.[39] The IL-17 family is thought to represent a distinct signalling system that appears to have been highly conserved across vertebrate evolution.[39]

List of human interleukins

Name Source [40] Target receptors[40][41] Target cells[40] Function[40]
IL-1 macrophages, B cells, monocytes,[42] dendritic cells [42] CD121a/IL1R1, CD121b/IL1R2 T helper cells co-stimulation [42]
B cells maturation & proliferation [42]
NK cells activation[42]
macrophages, endothelium, other inflammation,[42] small amounts induce acute phase reaction, large amounts induce fever
IL-2 Th1-cells CD25/IL2RA, CD122/IL2RB, CD132/IL2RG activated[42] 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.
IL-3 activated T helper cells,[42] mast cells, NK cells, endothelium, eosinophils CD123/IL3RA, CD131/IL3RB hematopoietic stem cells differentiation and proliferation of myeloid progenitor cells [42] to e.g. erythrocytes, granulocytes
mast cells growth and histamine release[42]
IL-4 Th2 cells, just activated naive CD4+ cell, memory CD4+ cells, mast cells, macrophages CD124/IL4R, CD132/IL2RG activated B cells proliferation and differentiation, IgG1 and IgE synthesis.[42] Important role in allergic response (IgE)
T cells proliferation[42]
endothelium increase expression of vascular cell adhesion molecule (VCAM-1) promoting adhesion of lymphocytes. [43]
IL-5 Th2 cells, mast cells, eosinophils CD125/IL5RA, CD131/IL3RB eosinophils production
B cells differentiation, IgA production
IL-6 macrophages, Th2 cells, B cells, astrocytes, endothelium 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 or CXCL8 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
IL-10 monocytes, Th2 cells, CD8+ T cells, mast cells, macrophages, B cell subset CD210/IL10RA, CDW210B/IL10RB macrophages cytokine production[42]
B cells activation [42]
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
IL-12 dendritic cells, B cells, T cells, macrophages CD212/IL12RB1, IR12RB2 activated [42] T cells, differentiation into Cytotoxic T cells with IL-2,[42]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 m,v,v,lkj,vn,, CDw218a/IL18R1 Th1 cells, NK cells Induces production of IFNγ, ↑ NK cell activity
IL-19 - IL20R -
IL-20 Activated keratinocytes and monocytes 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 T helper 17 cells (Th17) IL22R Production of defensins from epithelial cells.[32] 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 macrophages, dendritic cells IL23R Maintenance of IL-17 producing cells,[32] increases angiogenesis but reduces CD8 T-cell infiltration
IL-24 melanocytes, keratinocytes, monocytes, T cells IL20R Plays important roles in tumor suppression, wound healing and psoriasis by influencing cell survival, inflammatory cytokine expression.
IL-25 T Cells, mast cells, eosinophils, macrophages, mucosal epithelial cells LY6E Induces the production IL-4, IL-5 and IL-13, which stimulate eosinophil expansion
IL-26 T cells, monocytes IL20R1 Enhances secretion of IL-10 and IL-8 and cell surface expression of CD54 on epithelial cells
IL-27 macrophages, dendritic cells 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 Th2 cells 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
IL-36 - Regulates DC and T cell responses

INNs for pharmaceutical analogues and derivatives

Endogenous form name Pharmaceutical form INN suffix INNs
interleukin-1 (IL-1) -nakin
interleukin-1α (IL-1α) -onakin pifonakin
interleukin-1β (IL-1β) -benakin mobenakin
interleukin-2 (IL-2) -leukin adargileukin alfa, aldesleukin, celmoleukin, denileukin diftitox, pegaldesleukin, teceleukin, tucotuzumab celmoleukin
interleukin-3 (IL-3) -plestim daniplestim, muplestim
interleukin-4 (IL-4) -trakin binetrakin
interleukin-6 (IL-6) -exakin atexakin alfa
interleukin-8 (IL-8) -octakin emoctakin
interleukin-10 (IL-10) -decakin ilodecakin
interleukin-11 (IL-11) -elvekin oprelvekin
interleukin-12 (IL-12) -dodekin edodekin alfa
interleukin-13 (IL-13) -tredekin cintredekin besudotox
interleukin-18 (IL-18) -octadekin iboctadekin

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