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"). This decision was taken during a meeting in Interlaken, Switzerland.
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.
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.
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 IL-1 receptor type I 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. 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 receptor, the mice exhibit normal hippocampal-dependent memory function, and partial restoration of Long-term potentiation.
T Lymphocytes regulate the growth and differentiation of T cells and certain B cells through the release of 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. 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).
Interleukin 3 (IL3) is a cytokine that regulates blood-cell production by controlling the production, differentiation and function of granulocytes and macrophages. The protein, which exists in vivo as a monomer, is produced in activated T cells and mast cells, and is activated by the cleavage of an N-terminal signal sequence.
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. 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.
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 (IL5), also known as eosinophil differentiation factor (EDF), is a lineage-specific cytokine for eosinophilpoiesis. It regulates eosinophil growth and activation, and thus plays an important role in diseases associated with increased levels of eosinophils, including asthma. IL5 has a similar overall fold to other cytokines (e.g., IL2, IL4 and GCSF), 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.
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. 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. 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:. 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.
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 (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. 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 that has antiproliferative properties in human melanoma cells. Mda-7 contains only two of the four cysteines of IL-10.
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 (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 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.
Interleukin 13 (IL-13) is a pleiotropic cytokine that 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 (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 (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.
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.
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
^Ben Menachem-Zidon O, Avital A, Ben-Menahem Y, Goshen I, Kreisel T, Shmueli EM, Segal M, Ben Hur T, Yirmiya R (17 November 2010). "Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling". Brain, Behaviour, and Immunity25 (5): 1008–1016. doi:10.1016/j.bbi.2010.11.007. PMID21093580.
^Sims JE, March CJ, Cosman D, Widmer MB, MacDonald HR, McMahan CJ, Grubin CE, Wignall JM, Jackson JL, Call SM (July 1988). "cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily". Science241 (4865): 585–9. doi:10.1126/science.2969618. PMID2969618.
^Liu C, Hart RP, Liu XJ, Clevenger W, Maki RA, De Souza EB (August 1996). "Cloning and characterization of an alternatively processed human type II interleukin-1 receptor mRNA". J. Biol. Chem.271 (34): 20965–72. doi:10.1074/jbc.271.34.20965. PMID8702856.
^Murzin AG, Lesk AM, Chothia C (January 1992). "beta-Trefoil fold. Patterns of structure and sequence in the Kunitz inhibitors interleukins-1 beta and 1 alpha and fibroblast growth factors". J. Mol. Biol.223 (2): 531–43. doi:10.1016/0022-2836(92)90668-A. PMID1738162.
^ abBen Menachem-Zidon O, Avital A, Ben-Menahem Y, Goshen I, Kreisel T, Shmueli EM, Segal M, Ben Hur T, Yirmiya R (July 2011). "Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling". Brain Behav. Immun.25 (5): 1008–16. doi:10.1016/j.bbi.2010.11.007. PMID21093580.
^Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G, Yirmiya R (2003). "Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity". Hippocampus13 (7): 826–34. doi:10.1002/hipo.10135. PMID14620878.
^ abMott HR, Driscoll PC, Boyd J, Cooke RM, Weir MP, Campbell ID (1992). "Secondary structure of human interleukin 2 from 3D heteronuclear NMR experiments". Biochemistry31 (33): 7741–7744. doi:10.1021/bi00148a040. PMID1510960.
^ abDorssers L, Burger H, Bot F, Delwel R, Geurts van Kessel AH, Löwenberg B, Wagemaker G (1987). "Characterization of a human multilineage-colony-stimulating factor cDNA clone identified by a conserved noncoding sequence in mouse interleukin-3". Gene55 (1): 115–124. doi:10.1016/0378-1119(87)90254-X. PMID3497843.
^ abcdeYmer S, Tucker WQ, Sanderson CJ, Hapel AJ, Campbell HD, Young IG (1985). "Constitutive synthesis of interleukin-3 by leukaemia cell line WEHI-3B is due to retroviral insertion near the gene". Nature317 (6034): 255–258. doi:10.1038/317255a0. PMID2413359.
^ abcdMilburn MV, Hassell AM, Lambert MH, Jordan SR, Proudfoot AE, Graber P, Wells TN (1993). "A novel dimer configuration revealed by the crystal structure at 2.4 A resolution of human interleukin-5". Nature363 (6425): 172–176. doi:10.1038/363172a0. PMID8483502.
^ abProudfoot AE, Davies JG, Turcatti G, Wingfield PT (1991). "Human interleukin-5 expressed in Escherichia coli: assignment of the disulfide bridges of the purified unglycosylated protein". FEBS Lett.283 (1): 61–64. doi:10.1016/0014-5793(91)80553-F. PMID2037074.
^ abcHirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A (1986). "Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin". Nature324 (6092): 73–76. doi:10.1038/324073a0. PMID3491322.
^ abcLütticken C, Krüttgen A, Möller C, Heinrich PC, Rose-John S (1991). "Evidence for the importance of a positive charge and an alpha-helical structure of the C-terminus for biological activity of human IL-6". FEBS Lett.282 (2): 265–267. doi:10.1016/0014-5793(91)80491-K. PMID2037043.
^ abcClogston CL, Boone TC, Crandall BC, Mendiaz EA, Lu HS (1989). "Disulfide structures of human interleukin-6 are similar to those of human granulocyte colony stimulating factor". Arch. Biochem. Biophys.272 (1): 144–151. doi:10.1016/0003-9861(89)90205-1. PMID2472117.
^Walter MR, Cook WJ, Zhao BG, Cameron RP, Ealick SE, Walter RL, Reichert P, Nagabhushan TL, Trotta PP, Bugg CE (1992). "Crystal structure of recombinant human interleukin-4". J. Biol. Chem.267 (28): 20371–20376. PMID1400355.
^Renauld JC, Goethals A, Houssiau F, Merz H, Van Roost E, Van Snick J (1990). "Human P40/IL-9. Expression in activated CD4+ T cells, genomic organization, and comparison with the mouse gene". J. Immunol.144 (11): 4235–4241. PMID1971295.
^Zdanov A, Schalk-Hihi C, Gustchina A, Tsang M, Weatherbee J, Wlodawer A (1995). "Crystal structure of interleukin 10 reveals the functional dimer with an unexpected topological similarity to interferon gamma". Structure3 (6): 591–601. doi:10.1016/S0969-2126(01)00193-9. PMID8590020.
^Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB (1995). "Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression". Oncogene11 (12): 2477–2486. PMID8545104.
^Gately MK, Renzetti LM, Magram J, Stern AS, Adorini L, Gubler U, Presky DH (1998). "The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses". Annu. Rev. Immunol.16: 495–521. doi:10.1146/annurev.immunol.16.1.495. PMID9597139.
^Minty A, Chalon P, Derocq JM, Dumont X, Guillemot JC, Kaghad M, Labit C, Leplatois P, Liauzun P, Miloux B (1993). "Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses". Nature362 (6417): 248–250. doi:10.1038/362248a0. PMID8096327.