Cytokine and Cytokine Receptor Pleiotropy and Redundancy

interleukin granulocyte-macrophage colony-stimulating factor leukemia inhibitory factor oncostatin M ciliary neurotrophic factor novel neurotrophin-1/B cell-stimulating factor-3/cardiotrophin-like cytokine cardiotrophin-1 LIF receptor thymic stromal lymphopoietin X-linked severe combined immunodeficiency natural killer TSLP receptor interferon Cytokines represent a diverse group of molecules that collectively exert a wide range of actions (1Leonard W.J. Paul W.E. Fundamental Immunology. 4th Ed. Lippincott-Raven Publishers, Philadelphia1999: 741-774Google Scholar). The term cytokine is rather general, technically referring to a molecule made by one cell that acts on another, but cytokines are primarily growth factors and hormones of the immune and hematopoietic systems. The term broadly encompasses many of the interleukins and colony-stimulating factors (which are also referred to as type I cytokines) and interferons (which sometimes are referred to as type II cytokines) (1Leonard W.J. Paul W.E. Fundamental Immunology. 4th Ed. Lippincott-Raven Publishers, Philadelphia1999: 741-774Google Scholar). Certain molecules, such as erythropoietin, thrombopoietin, growth hormone, and prolactin, although not classically thought of as typical cytokines, have similar structures and signaling mechanisms to type I cytokines (1Leonard W.J. Paul W.E. Fundamental Immunology. 4th Ed. Lippincott-Raven Publishers, Philadelphia1999: 741-774Google Scholar). Many individual cytokines are themselves pleiotropic, exerting multiple actions, and particularly in vitro, many cytokines have overlapping actions (2Paul W.E. Cell. 1989; 57: 521-524Abstract Full Text PDF PubMed Scopus (200) Google Scholar, 3Leonard W.J. Curr Opin. Immunol. 1994; 6: 631-635Crossref PubMed Scopus (53) Google Scholar). There are multiple different possible mechanisms that can explain pleiotropic and overlapping actions for different cytokines. Pleiotropic actions can be explained by the presence of receptors for a cytokine on multiple lineages or by a cytokine having the ability to activate multiple signaling pathways wherein different signaling pathways differentially contribute to different functions. Overlapping actions by different cytokines can be explained by similar cellular distributions of specific receptors for different cytokines as well as by the sharing of signaling pathways, which particularly occurs when different receptors share similar motifs that mediate the coupling to the same pathways. In addition, however, cytokine pleiotropy and redundancy can be at least partially explained, respectively, by the ability of certain cytokines to signal via more than one type of receptor complex and by the sharing of an individual receptor component by more than one cytokine. We will herein summarize a range of different systems wherein cytokine receptor components are shared, discussing the implications thereof. For type I cytokines, these include the sharing of the common β chain, βc, by interleukin-3 (IL-3),1 IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF); the sharing of gp130 by IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), novel neurotrophin-1/B cell-stimulating factor-3/cardiotrophin-like cytokine (NNT-1/BSF-3/CLC), and cardiotrophin-1 (CT-1); the sharing of LIFRβ by LIF, OSM, CNTF, NNT-1/BSF-3/CLC, and CT-1; the sharing of CNTFRα by CNTF and NNT-1/BSF-3/CLC; the sharing of IL-12Rβ1 by IL-12 and IL-23; the sharing of γc by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; the sharing of IL-2Rβ by IL-2 and IL-15; the sharing of IL-4Rα and IL-13Rα1 by IL-4 and IL-13; and the sharing of IL-7Rα by IL-7 and thymic stromal lymphopoietin (TSLP) (Table I). The cytokines that can signal via more than one complex include IL-2, IL-4, human OSM, and murine IL-3. For type II cytokines, we discuss the sharing of IL-10Rβ by IL-10 and IL-22, the sharing of IL20Rα and IL-20Rβ by IL-19, IL-20, and IL-24, and the sharing of IL-22Rα by IL-20, IL-22, and IL-24.Table ISharing of receptor subunits by multiple type I cytokinesShared subunitOther componentsLigandIL-3RαβcHuman or murine IL-3βIL-3Murine IL-3βcIL-3RαIL-3GM-CSFRαGM-CSFIL-5RαIL-5gp130IL-6RαIL-6IL-11RαIL-11CNTFRα and LIFRβCTNFLIFRβLIFLIFRβOSM (human)OSMRβOSM (human or murine)LIFRβ and CNTFRαNNT-1/BSF-3/CLCLIFRβ and ?CT-1LIFRβgp130LIFgp130OSM (human)CNTFRα, gp130CNTFgp130 and CNTFRαNNT-1/BSF-3/CLCgp130 and ?CT-1CNTFRαgp130 and LIFRβCNTFgp130 and LIFRβNNT-1/BSF-3/ CLC plus CLF1IL-12Rβ1IL-12Rβ2IL-12IL-23RIL-23γcIL-2Rα, IL-2RβIL-2 (high affinity receptor)IL-2RβIL-2 (intermediate affinity receptor)IL-4RαIL-4IL-7RαIL-7IL-9RαIL-9IL-15Rα, IL-2RβIL-15IL-21RαIL-21IL-2RβγcIL-2 (high affinity receptor)IL-2Rα, γcIL-2 (intermediate affinity receptor)IL-15Rα, γcIL-15IL-4RαγcIL-4 (type I receptor)IL-13Rα1IL-4 (type II receptor)IL-13Rα1IL-4RαIL-4 (type II receptor)IL-4RαIL-13IL-7RαγcIL-7TSLPRTSLP Open table in a new tab The basic understanding of type I cytokine-receptor interactions comes from the original studies on growth hormone, a type I cytokine (4de Vos A.M. Ultsch M. Kossiakoff A.A. Science. 1992; 255: 306-312Crossref PubMed Scopus (2023) Google Scholar) (reviewed in Ref. 1Leonard W.J. Paul W.E. Fundamental Immunology. 4th Ed. Lippincott-Raven Publishers, Philadelphia1999: 741-774Google Scholar). Growth hormone was shown to bind to a growth hormone receptor homodimer; remarkably, two different parts of the ligand interacted with relatively similar regions of the receptor (4de Vos A.M. Ultsch M. Kossiakoff A.A. Science. 1992; 255: 306-312Crossref PubMed Scopus (2023) Google Scholar). The basic model is that growth hormone binds first to one monomer via a high affinity “Site 1” and then the second receptor monomer interacts with this complex, contacting growth hormone via “Site 2.” In the case of the growth hormone system, the complex is further stabilized via a receptor-receptor interaction site denoted as “Site 3” (4de Vos A.M. Ultsch M. Kossiakoff A.A. Science. 1992; 255: 306-312Crossref PubMed Scopus (2023) Google Scholar). Although this represents a homodimeric receptor system, it is easy to envision how receptor heterodimers would form if the second growth hormone receptor monomer were a distinctive receptor component. Such a second component is represented for example by the common cytokine receptor β chain (βc), gp130, and the common cytokine receptor γ chain (γc), which are discussed below. IL-3, IL-5, and GM-CSF are hematopoietic cytokines with IL-3 having actions as a “multi-CSF” on multiple lineages, IL-5 being essential for eosinophil expansion, and GM-CSF acting mainly on granulocytes and macrophages/monocytes. Each of these cytokines has a distinctive α chain (IL-3Rα, IL-5Rα, and GM-CSFRα), but they all share a common β chain, βc, in both humans and mice (5Hayashida K. Kitamura T. Gorman D.M. Arai K. Yokota T. Miyajima A. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 9655-9659Crossref PubMed Scopus (519) Google Scholar, 6Kitamura T. Sato N. Arai K. Miyajima A. 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Blood. 1996; 88: 2458-2464Crossref PubMed Google Scholar). IL-6, IL-11, LIF, OSM, CNTF, NNT-1/BSF-3/CLC, and CT-1 are seven cytokines, some of which were discovered in very different assay systems. Collectively, these cytokines exert multiple actions ranging from the immune system to the cardiovascular system to the central nervous system, but all of them share the gp130 signal-transducing molecule as a component of their receptors (13Taga T. Kishimoto T. Annu. Rev. Immunol. 1997; 15: 797-819Crossref PubMed Scopus (1298) Google Scholar, 14Miyajima A. Kinoshita T. Tanaka M. Kamiya A. Mukouyama Y. Hara T. Cytokine Growth Factor Rev. 2000; 11: 177-183Crossref PubMed Scopus (130) Google Scholar, 15Bravo J. Heath J.K. EMBO J. 2000; 19: 2399-2411Crossref PubMed Google Scholar, 16Senaldi G. Varnum B.C. Sarmiento U. Starnes C. Lile J. Scully S. Guo J. Elliott G. McNinch J. Shaklee C.L. Freeman D. Manu F. Simonet W.S. Boone T. Chang M.-S. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11458-11463Crossref PubMed Scopus (198) Google Scholar). IL-6 was originally identified as a B cell differentiation factor, but it also can exert effects related to T cell growth, and on many other cell types as well, including the induction of acute phase proteins. IL-11 is a stromal factor that can induce acute phase proteins and has a number of hematopoietic related effects as well, cooperating with IL-3 and stem cell factor. LIF can suppress the differentiation of pluripotent stem cells, inhibit monocyte differentiation of M1 cells, and inhibit adipogenesis, as well as exert effects in the central nervous system. LIF is identical to cholinergic neural differentiation factor. OSM was originally identified based on its ability to inhibit growth of a melanoma cell line, but it is also a growth potentiator, for example for Kaposi's sarcoma. CNTF is primarily known for its ability to promote neuronal survival. NNT-1/BSF-3/CLC also supports survival of chicken embryo motor and sympathetic neurons, whereas in mice it potentiates effects of IL-1 and IL-6 and has B cell stimulating capability. NNT-1/BSF-3/CLC associates with the soluble receptor cytokine-like factor-1 (CLF-1) as a second ligand for CNTFRα (17Elson G.C.A. Lelievre E. Guillet C. Chevalier S. Plun-Favreau H. Froger J. Suard I. de Cognac A.B. Delneste Y. Bonnefoy J.-Y. Gauchat J.-F. Gascan H. Nat. Neurosci. 2000; 3: 867-872Crossref PubMed Scopus (218) Google Scholar). Finally, although CT-1 was discovered based on its actions on cardiac muscle cells, it has a wide range of multifunctional roles, including actions with the hematopoietic and neural systems as well. Thus, a number of these factors have overlapping actions, but they are also distinctive. As noted above, these cytokines all share the gp130 signal-transducing molecule (13Taga T. Kishimoto T. Annu. Rev. Immunol. 1997; 15: 797-819Crossref PubMed Scopus (1298) Google Scholar, 14Miyajima A. Kinoshita T. Tanaka M. Kamiya A. Mukouyama Y. Hara T. Cytokine Growth Factor Rev. 2000; 11: 177-183Crossref PubMed Scopus (130) Google Scholar, 15Bravo J. Heath J.K. EMBO J. 2000; 19: 2399-2411Crossref PubMed Google Scholar, 16Senaldi G. Varnum B.C. Sarmiento U. Starnes C. Lile J. Scully S. Guo J. Elliott G. McNinch J. Shaklee C.L. Freeman D. Manu F. Simonet W.S. Boone T. Chang M.-S. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11458-11463Crossref PubMed Scopus (198) Google Scholar). gp130 was originally cloned as a component, along with IL-6Rα, of the IL-6 receptor (13Taga T. Kishimoto T. Annu. Rev. Immunol. 1997; 15: 797-819Crossref PubMed Scopus (1298) Google Scholar). The IL-11 receptor contains IL-11Rα and gp130; the LIF receptor contains LIFRβ and gp130; oncostatin M can act via receptors containing either OSMRβ and gp130 or LIFRβ and gp130; the CNTF receptor contains CNTFRα, LIFRβ, and gp130; the NNT-1/BSF-3/CLC receptor contains CNTFRα, LIFRβ, and gp130; and the CT-1 receptor contains LIFRβ and gp130. Thus, IL-6 and IL-11 do not use LIFRβ, whereas LIF, OSM, CNTF, NNT-1/BSF-3/CLC, and CT-1 do. As noted, human OSM can signal through two types of receptors, one of which uses LIFRβ and one of which does not. As part of an investigation of IL-6 signaling, the gene encoding gp130 was disrupted in mice. Unexpectedly, in addition to certain defects in hematopoiesis, targeting of gp130 resulted in a fetal-lethal phenotype because of a defect in myocardial development (18Yoshida K. Taga T. Saito M. Suematsu S. Kumanogoh A. Tanaka T. Fujiwara H. Hirata M. Yamagami T. Nakahata T. Hirabayashi T. Yoneda Y. Tanaka K. Wang W.Z. Mori C. Shiota K. Yoshida N. 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Immunol. PubMed Scopus Google Scholar, H. D. M. A. 15: PubMed Scopus Google Scholar, Y. K. T. T. M. Kitamura T. 93: PubMed Scopus (53) Google Scholar). with the and IL-19, IL-20, denoted for T denoted as for melanoma gene and are as type II cytokines (reviewed in Vos A.M. Ultsch M. Kossiakoff A.A. Science. 1992; 255: 306-312Crossref PubMed Scopus (2023) Google K.W. de Waal Malefyt R. A. Annu. Rev. Immunol. 19: PubMed Scopus Google Scholar, L. C. D. J. Immunol. PubMed Scopus Google Scholar, M. Zhang R. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, H. S. H. A. S. H. Immunol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). IL-10 was the first of these molecules discovered as a that inhibit the of cytokines K.W. de Waal Malefyt R. A. Annu. Rev. Immunol. 19: PubMed Scopus Google Scholar). The receptor for IL-10 consists of plus The of cytokines exert a range of actions, partially as is based on the sharing of receptor K.W. de Waal Malefyt R. A. Annu. Rev. Immunol. 19: PubMed Scopus Google Scholar, L. C. D. J. Immunol. PubMed Scopus Google Scholar, M. Zhang R. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, H. S. H. A. S. H. Immunol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) as in of receptor subunits by multiple type II cytokinesShared subunitOther Open table in a new tab I and type II cytokines exhibit both cytokine pleiotropy and There are multiple wherein these cytokines share receptor This can be as cytokine receptor wherein a chain such as βc, gp130, LIFRβ, CNTFRα, CNTFRα, or IL-22Rα as part of more than a receptor. In addition, there are of can be as possible cytokine receptor wherein more than one receptor form can for a cytokine. include the and high affinity forms of the IL-2 type I and type II IL-4 receptors, murine IL-3 receptors that use either βc or βIL-3, and two forms of OSM, IL-20, and these represent receptor forms for or instead represent two forms of receptors that exert distinctive actions is for IL-2 wherein the affinity form is on whereas the high affinity form is essential for the of T further how similar many type I cytokines are to other and the of multiple type I cytokine receptor it is possible that of the cytokines and their receptor is a that has the of new distinctive cytokine functions. The same is also to interferons and the IL-10 of type II cytokines. As on the of cytokine-receptor a understanding of these systems will This the specific for the ability of cytokines to with more than one receptor and the ability of a receptor chain to with multiple cytokines.