Cytokine and Cytokine Receptor Pleiotropy and Redundancy
2002; Elsevier BV; Volume: 277; Issue: 33 Linguagem: Inglês
10.1074/jbc.r200003200
ISSN1083-351X
AutoresKatsutoshi Ozaki, Warren J. Leonard,
Tópico(s)T-cell and B-cell Immunology
Resumointerleukin 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. Cell. 1991; 66: 1165-1174Abstract Full Text PDF PubMed Scopus (509) Google Scholar, 7Tavernier J. Devos R. Cornelis S. Tuypens T. Van der Heyden J. Fiers W. Plaetinck G. Cell. 1991; 66: 1175-1184Abstract Full Text PDF PubMed Scopus (497) Google Scholar) (reviewed in Ref. 8Miyajima A. Mui A.L. Ogorochi T. Sakamaki K. Blood. 1993; 82: 1960-1974Crossref PubMed Google Scholar). Interestingly, in mice but not in humans there is an IL-3-specific β chain as well, denoted βIL-3 (8Miyajima A. Mui A.L. Ogorochi T. Sakamaki K. Blood. 1993; 82: 1960-1974Crossref PubMed Google Scholar, 9Itoh N. Yonehara S. Schreurs J. Gorman D.M. Maruyama K. Ishii A. Yahara I. Arai K. Miyajima A. Science. 1990; 247: 324-327Crossref PubMed Scopus (290) Google Scholar). Despite the presumed importance of IL-3, IL-5, and GM-CSF for hematopoiesis, disruption of βc in a murine knock-out model does not cause a severe defect within the hematopoietic system, although signaling in response to IL-5 and GM-CSF is disrupted, and these mice exhibit alveolar proteinosis and defective eosinophil responses (10Nishinakamura R. Nakayama N. Hirabayashi Y. Inoue T. Aud D. McNeil T. Azuma S. Yoshida S. Toyoda Y. Arai K. et al.Immunity. 1995; 2: 211-222Abstract Full Text PDF PubMed Scopus (272) Google Scholar, 11Robb L. Drinkwater C.C. Metcalf D., Li, R. Kontgen F. Nicola N.A. Begley C.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9565-9569Crossref PubMed Scopus (248) Google Scholar). As expected, signaling in response to IL-3 remains normal because of the presence of βIL-3, with IL-3 signaling being eliminated only in the context of βc/IL-3 double knock-out mice (12Nishinakamura R. Miyajima A. Mee P.J. Tybulewicz V.L. Murray R. 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. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 407-411Crossref PubMed Scopus (573) Google Scholar). This phenotype presumably does not relate to a defect in IL-6 signaling but instead may relate to other cytokines such as CT-1. LIFRβ gene disruption results in a neural defect (19Li M. Sendtner M. Smith A. Nature. 1995; 378: 724-727Crossref PubMed Scopus (276) Google Scholar, 20Ware C.B. Horowitz M.C. Renshaw B.R. Hunt J.S. Liggitt D. Koblar S.A. Gliniak B.C. McKenna H.J. Papayannopoulou T. Thoma B. et al.Development. 1995; 121: 1283-1299Crossref PubMed Google Scholar). IL-12 is structurally an interesting cytokine that consists of an IL-6-like cytokine, p35, that associates with p40, a protein that resembles a soluble cytokine receptor. The p35-p40 heterodimer signals through a receptor that consists of IL-12Rβ1 and IL-12Rβ2 and is important for Th1 cell differentiation (21Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1103) Google Scholar, 22Trinchieri G. Adv. Immunol. 1998; 70: 83-243Crossref PubMed Google Scholar). More recently, another IL-12 p40 partner, denoted p19, was identified (23Oppmann B. Lesley R. Blom B. Timans J.C., Xu, Y. Hunte B. Vega F., Yu, N. Wang J. Singh K. Zonin F. Vaisberg E. Churakova T. Liu M. Gorman D. Wagner J. Zurawski S. Liu Y.-J. Abrams J.S. Moore K.W. Rennick D. de Waal-Malefyt R. Hannum C. Bazan J.F. Kastelein R.A. Immunity. 2000; 13: 715-725Abstract Full Text Full Text PDF PubMed Scopus (2285) Google Scholar). The p19/p40 dimer forms IL-23, which signals via IL-12Rβ1 and IL-23R (71Parham C. Chirica M. Timans J. Vaisberg E. Travis M. Cheung J. Pflanz S. Zhang R. Singh K.P. Vega F., To, W. Wagner J. O'Farrell A.-M. McClanahan T. Zurawski S. Hannum C. Gorman D. Rennick D.M. Kastelein R.A. de Waal Malefyt R. Moore K.W. J. Immunol. 2002; 168: 5699-5708Crossref PubMed Scopus (1082) Google Scholar) but not IL-12Rβ2. Like IL-12, IL-23 activates Stat4 (23Oppmann B. Lesley R. Blom B. Timans J.C., Xu, Y. Hunte B. Vega F., Yu, N. Wang J. Singh K. Zonin F. Vaisberg E. Churakova T. Liu M. Gorman D. Wagner J. Zurawski S. Liu Y.-J. Abrams J.S. Moore K.W. Rennick D. de Waal-Malefyt R. Hannum C. Bazan J.F. Kastelein R.A. Immunity. 2000; 13: 715-725Abstract Full Text Full Text PDF PubMed Scopus (2285) Google Scholar). The common cytokine receptor γ chain (γc) was originally cloned as a third component of the IL-2 receptor and thus denoted as the IL-2Rγ chain, corresponding to α-β nomenclature of the first chains that were discovered (24Takeshita T. Asao H. Ohtani K. Ishii N. Kumaki S. Tanaka N. Munakata H. Nakamura M. Sugamura K. Science. 1992; 257: 379-382Crossref PubMed Scopus (813) Google Scholar). Noguchi et al.(25Noguchi M., Yi, H. Rosenblatt H.M. Filipovich A.H. Adelstein S. Modi W.S. McBride O.W. Leonard W.J. Cell. 1993; 73: 147-157Abstract Full Text PDF PubMed Scopus (1164) Google Scholar) then discovered that mutations in IL-2Rγ resulted in X-SCID (also denoted as SCID-X1), a disease characterized by profoundly diminished numbers of T cells and NK cells but with normal albeit non-functional B cells (T−B+NK−SCID). A defect in a component of the IL-2 receptor in this disease was unexpected given that humans and mice lacking expression of the IL-2 gene exhibited normal T cell and NK cell development (26Schorle H. Holtschke T. Hunig T. Schimpl A. Horak I. Nature. 1991; 352: 621-624Crossref PubMed Scopus (787) Google Scholar, 27Pahwa R. Chatila T. Pahwa S. Paradise C. Day N.K. Geha R. Schwartz S.A. Slade H. Oyaizu N. Good R.A. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 5069-5073Crossref PubMed Scopus (85) Google Scholar, 28Weinberg K. Parkman R. N. Engl. J. Med. 1990; 322: 1718-1723Crossref PubMed Scopus (130) Google Scholar). Thus, it was predicted that IL-2Rγ must exert additional actions beyond the IL-2 system (25Noguchi M., Yi, H. Rosenblatt H.M. Filipovich A.H. Adelstein S. Modi W.S. McBride O.W. Leonard W.J. Cell. 1993; 73: 147-157Abstract Full Text PDF PubMed Scopus (1164) Google Scholar), and indeed it was found that IL-2Rγ was a component of other cytokine receptors as well, resulting in the changing of its name to γc. In addition to IL-2, the receptors for IL-4, IL-7, IL-9, IL-15, and IL-21 also contain γc (reviewed in Ref. 29Leonard W.J. Nature Rev. Immunol. 2001; 1: 200-208Crossref PubMed Scopus (305) Google Scholar) (Fig. 1A), and this family of cytokines is sometimes denoted as the IL-2 family of cytokines. The phenotypes of Il7−/− (30von Freeden-Jeffry U. Vieira P. Lucian L.A. McNeil T. Burdach S.E. Murray R. J. Exp. Med. 1995; 181: 1519-1526Crossref PubMed Scopus (1253) Google Scholar) and Il7r−/− (31Peschon J.J. Morrissey P.J. Grabstein K.H. Ramsdell F.J. Maraskovsky E. Gliniak B.C. Park L.S. Ziegler S.F. Williams D.E. Ware C.B. Mayer J.D. Davison B.L. J. Exp. Med. 1994; 180: 1955-1960Crossref PubMed Scopus (1335) Google Scholar) mice as well as that of humans with mutations in the human IL7R gene have revealed that the lack of T cells in X-SCID results from defective IL-7 signaling (32Puel A. Ziegler S.F. Buckley R.H. Leonard W.J. Nat. Genet. 1998; 20: 394-397Crossref PubMed Scopus (691) Google Scholar). A range of in vitro experiments as well as the phenotype of mice lacking expression of either IL-15 or IL-15Rα together indicate that defective NK cell development results from defective IL-15 signaling (33Cavazzana-Calvo M. Hacein-Bey S. de Saint Basile G., De Coene C. Selz F., Le Deist F. Fischer A. Blood. 1996; 88: 3901-3909Crossref PubMed Google Scholar, 34Kennedy M.K. Glaccum M. Brown S.N. Butz E.A. Viney J.L. Embers M. Matsuki N. Charrier K. Sedger L. Willis C.R. Brasel K. Morrissey P.J. Stocking K. Schuh J.C. Joyce S. Peschon J.J. J. Exp. Med. 2000; 191: 771-780Crossref PubMed Scopus (1342) Google Scholar, 35Lodolce J.P. Boone D.L. Chai S. Swain R.E. Dassopoulos T. Trettin S. Ma A. Immunity. 1998; 9: 669-676Abstract Full Text Full Text PDF PubMed Scopus (1095) Google Scholar). All six of the γc-dependent cytokines have the ability to act, at least in vitro, as T cell growth factors (29Leonard W.J. Nature Rev. Immunol. 2001; 1: 200-208Crossref PubMed Scopus (305) Google Scholar). IL-2 is the major T cell growth factor that allows T cell expansion following antigen encounter, but it also plays additional major roles, including for example in antigen-induced cell death and in the boosting of natural killer cytolytic activity (1Leonard W.J. Paul W.E. Fundamental Immunology. 4th Ed. Lippincott-Raven Publishers, Philadelphia1999: 741-774Google Scholar). IL-4 is essential for T helper 2 (Th2) cell differentiation and for immunoglobulin class switch (36Kopf M., Le Gros G. Bachmann M. Lamers M.C. Bluethmann H. Kohler G. Nature. 1993; 362: 245-248Crossref PubMed Scopus (1095) Google Scholar). IL-7 is essential for T cell development in both humans and mice and for B cell development in mice but not humans. IL-9 is important for mast cell growth and mucous production (37Townsend J.M. Fallon G.P. Matthews J.D. Smith P. Jolin E.H. McKenzie N.A. Immunity. 2000; 13: 573-583Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). IL-15 is essential for NK cell development and memory CD8 T cell expansion (34Kennedy M.K. Glaccum M. Brown S.N. Butz E.A. Viney J.L. Embers M. Matsuki N. Charrier K. Sedger L. Willis C.R. Brasel K. Morrissey P.J. Stocking K. Schuh J.C. Joyce S. Peschon J.J. J. Exp. Med. 2000; 191: 771-780Crossref PubMed Scopus (1342) Google Scholar, 35Lodolce J.P. Boone D.L. Chai S. Swain R.E. Dassopoulos T. Trettin S. Ma A. Immunity. 1998; 9: 669-676Abstract Full Text Full Text PDF PubMed Scopus (1095) Google Scholar, 38Zhang X. Sun S. Hwang I. Tough D.F. Sprent J. Immunity. 1998; 8: 591-599Abstract Full Text Full Text PDF PubMed Scopus (1060) Google Scholar). The role of IL-21, a more recently identified cytokine, is not yet sufficiently understood in vivo. The IL-21 binding protein, IL-21R, is most similar to IL-2Rβ (39Ozaki K. Kristine K. Michalovich D. Young P.R. Leonard W.J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 11439-11444Crossref PubMed Scopus (275) Google Scholar, 40Parrish-Novak J. Dillon S.R. Nelson A. Hammond A. Sprecher C. Gross J.A. Johnston J. Madden K., Xu, W. West J. Schrader S. Burkhead S. Heipel M. Brandt C. Kuijper J.L. Kramer J. Conklin D. Presnell S.R. Berry J. Shiota F. Bort S. Hambly K. Mudri S. Clegg C. Moore M. Grant F.J. Lofton-Day C. Nature. 2000; 408: 57-63Crossref PubMed Scopus (996) Google Scholar). In vitro, IL-21 has a co-stimulatory effect on anti-CD3 T cell proliferation, can augment anti-CD40-induced B cell proliferation, and can inhibit B cell proliferation induced by anti-IgM plus IL-4 (40Parrish-Novak J. Dillon S.R. Nelson A. Hammond A. Sprecher C. Gross J.A. Johnston J. Madden K., Xu, W. West J. Schrader S. Burkhead S. Heipel M. Brandt C. Kuijper J.L. Kramer J. Conklin D. Presnell S.R. Berry J. Shiota F. Bort S. Hambly K. Mudri S. Clegg C. Moore M. Grant F.J. Lofton-Day C. Nature. 2000; 408: 57-63Crossref PubMed Scopus (996) Google Scholar). It was also reported to augment the maturation of CD56+ cytolytic NK cells from human bone marrow CD34+ cells in vitro in response to Flt-3 ligand plus IL-15 (40Parrish-Novak J. Dillon S.R. Nelson A. Hammond A. Sprecher C. Gross J.A. Johnston J. Madden K., Xu, W. West J. Schrader S. Burkhead S. Heipel M. Brandt C. Kuijper J.L. Kramer J. Conklin D. Presnell S.R. Berry J. Shiota F. Bort S. Hambly K. Mudri S. Clegg C. Moore M. Grant F.J. Lofton-Day C. Nature. 2000; 408: 57-63Crossref PubMed Scopus (996) Google Scholar), but a more recent report suggests that it may instead oppose the actions of IL-15 (41Kasaian M.T. Whitters M.J. Carter L.L. Lowe L.D. Jussif J.M. Deng B. Johnson K.A. Witek J.S. Senices M. Konz R.F. Wurster A.L. Donaldson D.D. Collins M. Young D.A. Grusby M.J. Immunity. 2002; 16: 559-569Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar). IL-21R seems to be expressed primarily in lymphoid tissue such as thymus and spleen (39Ozaki K. Kristine K. Michalovich D. Young P.R. Leonard W.J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 11439-11444Crossref PubMed Scopus (275) Google Scholar, 40Parrish-Novak J. Dillon S.R. Nelson A. Hammond A. Sprecher C. Gross J.A. Johnston J. Madden K., Xu, W. West J. Schrader S. Burkhead S. Heipel M. Brandt C. Kuijper J.L. Kramer J. Conklin D. Presnell S.R. Berry J. Shiota F. Bort S. Hambly K. Mudri S. Clegg C. Moore M. Grant F.J. Lofton-Day C. Nature. 2000; 408: 57-63Crossref PubMed Scopus (996) Google Scholar). IL-21R levels are induced by T cell receptor stimulation in human peripheral blood mononuclear cells (39Ozaki K. Kristine K. Michalovich D. Young P.R. Leonard W.J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 11439-11444Crossref PubMed Scopus (275) Google Scholar). There are three types of receptors for IL-2: the low affinity receptor (containing IL-2Rα), intermediate affinity receptor (containing IL-2Rβ and γc), and high affinity receptor (containing IL-2Rα, IL-2Rβ, and γc) (reviewed in Refs. 1Leonard W.J. Paul W.E. Fundamental Immunology. 4th Ed. Lippincott-Raven Publishers, Philadelphia1999: 741-774Google Scholar and 29Leonard W.J. Nature Rev. Immunol. 2001; 1: 200-208Crossref PubMed Scopus (305) Google Scholar). The intermediate and high affinity receptors are the functional forms. The “type I” IL-4 receptor on T cells contains IL-4Rα plus γc, but there is a second functional IL-4 receptor (“type II IL-4 receptor”; see next section). The IL-7 receptor contains IL-7Rα plus γc. The IL-9 receptor contains IL-9Rα plus γc. The IL-15 receptor contains IL-15Rα, IL-2Rβ, and γc; thus, both the IL-2 and IL-15 receptors contain both IL-2Rβ and γc and differ only in distinctive α chains. Finally, the IL-21 receptor contains IL-21Rα plus γc (reviewed in Ref. 29Leonard W.J. Nature Rev. Immunol. 2001; 1: 200-208Crossref PubMed Scopus (305) Google Scholar). IL-4 is closely related to another T cell-derived cytokine, IL-13. As noted above, the type I IL-4 receptor contains IL-4Rα plus γc. IL-4Rα was cloned originally as a receptor for IL-4 (42Mosley B. Beckmann M.P. March C.J. Idzerda R.L. Gimpel S.D. VandenBos T. Friend D. Alpert A. Anderson D. Jackson J. et al.Cell. 1989; 59: 335-348Abstract Full Text PDF PubMed Scopus (486) Google Scholar). Overlapping actions of IL-4 and IL-13 and a range of other data, including the activation of the same STAT protein (Stat6) and the ability of IL-4 and IL-13 to cross-compete for binding had suggested that IL-4 and IL-13 would share a receptor component (43Zurawski S.M. Vega F., Jr. Huyghe B. Zurawski G. EMBO J. 1993; 12: 2663-2670Crossref PubMed Scopus (441) Google Scholar, 44Aversa G. Punnonen J. Cocks B.G. de Waal Malefyt R. Vega F., Jr. Zurawski S.M. Zurawski G. de Vries J.E. J. Exp. Med. 1993; 178: 2213-2218Crossref PubMed Scopus (194) Google Scholar, 45Renard N. Duvert V. Banchereau J. Saeland S. Blood. 1994; 84: 2253-2260Crossref PubMed Google Scholar, 46Lin J.X. Migone T.S. Tsang M. Friedmann M. Weatherbee J.A. Zhou L. Yamauchi A. Bloom E.T. Mietz J. John S. et al.Immunity. 1995; 2: 331-339Abstract Full Text PDF PubMed Scopus (677) Google Scholar, 47Smerz-Bertling C. Duschl A. J. Biol. Chem. 1995; 270: 966-970Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar) (reviewed in Ref. 48Callard R.E. Matthews D.J. Hibbert L. Immunol. Today. 1996; 17: 108-110Abstract Full Text PDF PubMed Scopus (167) Google Scholar). Interestingly, the type II IL-4 receptor, present on fibroblasts and certain other cell types, consists of IL-4Rα plus IL-13Rα1, and this complex also is the functional IL-13 receptor (49Hilton D.J. Zhang J.G. Metcalf D. Alexander W.S. Nicola N.A. Willson T.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 497-501Crossref PubMed Scopus (390) Google Scholar,50Aman M.J. Tayebi N. Obiri N.I. Puri R.K. Modi W.S. Leonard W.J. J. Biol. Chem. 1996; 271: 29265-29270Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar) (Fig. 1B). Interestingly, whereas IL-4 primarily binds IL-4Rα, IL-13 primarily binds IL-13Rα1. There is a second IL-13 binding protein called IL-13Rα2, which binds IL-13 with even higher affinity than IL-13Rα1 but which appears to be a non-functional inhibitory “decoy” receptor (51Caput D. Laurent P. Kaghad M. Lelias J.M. Lefort S. Vita N. Ferrara P. J. Biol. Chem. 1996; 271: 16921-16926Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 52Donaldson D.D. Whitters M.J. Fitz L.J. Neben T.Y. Finnerty H. Henderson S.L. O'Hara R.M., Jr. Beier D.R. Turner K.J. Wood C.R. Collins M. J. Immunol. 1998; 161: 2317-2324PubMed Google Scholar). Both IL-4 and IL-13 appear to be important for Th2 differentiation asIl13−/− mice also show a Th2 differentiation defect (53McKenzie G.J. Emson C.L. Bell S.E. Anderson S. Fallon P. Zurawski G. Murray R. Grencis R. McKenzie A.N. Immunity. 1998; 9: 423-432Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar). As expected, disruption of the Il4ra gene in mice results in defective Th2 differentiation (54Noben-Trauth N. Shultz L.D. Brombacher F. Urban J.F., Jr., Gu, H. Paul W.E. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10838-10843Crossref PubMed Scopus (287) Google Scholar). In addition to its contribution to Th2 differentiation, IL-13 is essential for worm expulsion and for antigen-induced asthma (55McKenzie G.J. Bancroft A. Grencis R.K. McKenzie A.N. Curr. Biol. 1998; 8: 339-342Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar, 56Wills-Karp M. Luyimbazi J., Xu, X. Schofield B. Neben T.Y. Karp C.L. Donaldson D.D. Science. 1998; 282: 2258-2261Crossref PubMed Scopus (2390) Google Scholar, 57Grunig G. Warnock M. Wakil A.E. Venkayya R. Brombacher F. Rennick D.M. Sheppard D. Mohrs M. Donaldson D.D. Locksley R.M. Corry D.B. Science. 1998; 282: 2261-2263Crossref PubMed Scopus (1732) Google Scholar). TSLP was identified as a factor that was present in the medium of a thymic stromal cell line, Z210R.1, and was capable of supporting the growth of a pre-B cell line, NAG8/7 (58Friend S.L. Hosier S. Nelson A. Foxworthe D. Williams D.E. Farr A. Exp. Hematol. 1994; 22: 321-328PubMed Google Scholar). Interestingly, the receptor for TSLP contains its own distinctive receptor chain, TSLPR, as well as IL-7Rα (59Pandey A. Ozaki K. Baumann H. Levin S.D. Puel A. Farr A.G. Ziegler S.F. Leonard W.J. Lodish H.F. Nature Immunol. 2000; 1: 59-64Crossref PubMed Scopus (342) Google Scholar, 60Park L.S. Martin U. Garka K. Gliniak B., Di Santo J.P. Muller W. Largaespada D.A. Copeland N.G. Jenkins N.A. Farr A.G. Ziegler S.F. Morrissey P.J. Paxton R. Sims J.E. J. Exp. Med. 2000; 192: 659-670Crossref PubMed Scopus (328) Google Scholar). Thus, TSLP and IL-7 share IL-7Rα as a common receptor component (Fig. 1C). This helps to explain why the phenotype of Il7r−/− mice is somewhat more severe than that seen in Il7−/− mice, because the former inactivates signaling in response to both IL-7 and TSLP and the latter only signaling in response to IL-7. Interestingly, IL-13Rα1, which can substitute for γc in the context of IL4 signaling, and TSLPR, which “replaces” γc as one transitions from IL-7 to TSLP signaling, are both similar to γc. This is particularly true of TSLPR, which is the protein in public data bases with highest amino acid similarity to γc (59Pandey A. Ozaki K. Baumann H. Levin S.D. Puel A. Farr A.G. Ziegler S.F. Leonard W.J. Lodish H.F. Nature Immunol. 2000; 1: 59-64Crossref PubMed Scopus (342) Google Scholar). TSLPR was cloned by four groups (59Pandey A. Ozaki K. Baumann H. Levin S.D. Puel A. Farr A.G. Ziegler S.F. Leonard W.J. Lodish H.F. Nature Immunol. 2000; 1: 59-64Crossref PubMed Scopus (342) Google Scholar, 60Park L.S. Martin U. Garka K. Gliniak B., Di Santo J.P. Muller W. Largaespada D.A. Copeland N.G. Jenkins N.A. Farr A.G. Ziegler S.F. Morrissey P.J. Paxton R. Sims J.E. J. Exp. Med. 2000; 192: 659-670Crossref PubMed Scopus (328) Google Scholar, 61Fujio K. Nosaka T. Kojima T. Kawashima T. Yahata T. Copeland N.G. Gilbert D.J. Jenkins N.A. Yamamoto K. Nishimura T. Kitamura T. Blood. 2000; 95: 2204-2210Crossref PubMed Google Scholar, 62Hiroyama T. Iwama A. Morita Y. Nakamura Y. Shibuya A. Nakauchi H. Biochem. Biophys. Res. Commun. 2000; 272: 224-229Crossref PubMed Scopus (32) Google Scholar). Two groups reported the gene as one that encodes an orphan receptor (61Fujio K. Nosaka T. Kojima T. Kawashima T. Yahata T. Copeland N.G. Gilbert D.J. Jenkins N.A. Yamamoto K. Nishimura T. Kitamura T. Blood. 2000; 95: 2204-2210Crossref PubMed Google Scholar, 62Hiroyama T. Iwama A. Morita Y. Nakamura Y. Shibuya A. Nakauchi H. Biochem. Biophys. Res. Commun. 2000; 272: 224-229Crossref PubMed Scopus (32) Google Scholar). A third group identified it as an expressed sequence tag (EST) that had substantial homology to the erythropoietin receptor cytoplasmic domain, but then it was directly demonstrated that this orphan receptor was in fact the elusive TSLPR (59Pandey A. Ozaki K. Baumann H. Levin S.D. Puel A. Farr A.G. Ziegler S.F. Leonard W.J. Lodish H.F. Nature Immunol. 2000; 1: 59-64Crossref PubMed Scopus (342) Google Scholar). Another group reported the cloning of TSLP as well as its receptor (60Park L.S. Martin U. Garka K. Gliniak B., Di Santo J.P. Muller W. Largaespada D.A. Copeland N.G. Jenkins N.A. Farr A.G. Ziegler S.F. Morrissey P.J. Paxton R. Sims J.E. J. Exp. Med. 2000; 192: 659-670Crossref PubMed Scopus (328) Google Scholar, 63Sims J.E. Williams D.E. Morrissey P.J. Garka K. Foxworthe D. Price V. Friend S.L. Farr A. Bedell M.A. Jenkins N.A. Copeland N.G. Grabstein K. Paxton R.J. J. Exp. Med. 2000; 192: 671-680Crossref PubMed Scopus (188) Google Scholar). TSLP only weakly binds to TSLPR but exhibits higher affinity to the combination of TSLPR and IL-7Rα. TheKd of TSLP binding to its receptor varies in different cell lines: the Kd values for NAG8/7, 70Z/3, and 7B9 were 2.2, 7.1, and 0.1 nm, respectively (59Pandey A. Ozaki K. Baumann H. Levin S.D. Puel A. Farr A.G. Ziegler S.F. Leonard W.J. Lodish H.F. Nature Immunol. 2000; 1: 59-64Crossref PubMed Scopus (342) Google Scholar,63Sims J.E. Williams D.E. Morrissey P.J. Garka K. Foxworthe D. Price V. Friend S.L. Farr A. Bedell M.A. Jenkins N.A. Copeland N.G. Grabstein K. Paxton R.J. J. Exp. Med. 2000; 192: 671-680Crossref PubMed Scopus (188) Google Scholar); the basis for the differences is unknown but perhaps relates to different levels of expression of the different receptor components in each cell line. TSLP supports and expands IgM+ B cells in vitro, as reported previously (58Friend S.L. Hosier S. Nelson A. Foxworthe D. Williams D.E. Farr A. Exp. Hematol. 1994; 22: 321-328PubMed Google Scholar) and also in vivo. It also appears to have a minimal supporting activity for growth of thymocytes (63Sims J.E. Williams D.E. Morrissey P.J. Garka K. Foxworthe D. Price V. Friend S.L. Farr A. Bedell M.A. Jenkins N.A. Copeland N.G. Grabstein K. Paxton R.J. J. Exp. Med. 2000; 192: 671-680Crossref PubMed Scopus (188) Google Scholar). Human TSLP and TSLPR were cloned, and human TSLP was found to augment the maturation of dendritic cells and to induce chemokine production in monocytes (64Reche P.A. Soumelis V. Gorman D.M. Clifford T. Liu M-r. Travis M. Zurawski S.M. Johnston J. Liu Y.J. Spits H. de Waal Malefyt R. Kastelein R.A. Bazan J.F. J. Immunol. 2001; 167: 336-343Crossref PubMed Scopus (332) Google Scholar, 65Quentmeier H. Drexler H.G. Fleckenstein D. Zaborski M. Armstrong A. Sims J.E. Lyman S.D. Leukemia. 2001; 15: 1286-1292Crossref PubMed Scopus (150) Google Scholar, 66Tonozuka Y. Fujio K. Sugiyama T. Nosaka T. Hirai M. Kitamura T. Cytogenet. Cell Genet. 2001; 93: 23-25Crossref PubMed Scopus (53) Google Scholar). Together with the IFNs (IFNα, IFNβ, IFNγ, IFNω, and IFNτ), IL-10, IL-19, IL-20, IL-22 (formerly denoted IL-TIF for IL-10-related T cell-derived inducible factor), IL-24 (formerly denoted as mda-7 for melanoma differentiation-associated gene 7), and IL-26 (AK 155) are designated as type II cytokines (reviewed in Refs. 4de Vos A.M. Ultsch M. Kossiakoff A.A. Science. 1992; 255: 306-312Crossref PubMed Scopus (2023) Google Scholar and67Moore K.W. de Waal Malefyt R. Coffman R.L. O'Garra A. Annu. Rev. Immunol. 2001; 19: 683-765Crossref PubMed Scopus (5322) Google Scholar, 68Dumoutier L. Leemans C. Lejeune D. Kotenko S.V. Renauld J.-C. J. Immunol. 2001; 167: 3545-3549Crossref PubMed Scopus (357) Google Scholar, 69Wang M. Tan Z. Zhang R. Kotenko S.V. Liang P. J. Biol. Chem. 2002; 277: 7341-7347Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 70Fickenscher H. Hor S. Kupers H. Knappe A. Wittmann S. Sticht H. Trends Immunol. 2002; 23: 89-96Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). IL-10 was the first of these molecules discovered as a potent immunomodulator that could inhibit the production of pro-inflammatory cytokines (67Moore K.W. de Waal Malefyt R. Coffman R.L. O'Garra A. Annu. Rev. Immunol. 2001; 19: 683-765Crossref PubMed Scopus (5322) Google Scholar). The receptor for IL-10 consists of IL-10Rα plus IL-10Rβ. The array of IL-10-related cytokines exert a range of actions, partially overlapping, as is logical based on the extensive sharing of receptor chains (67Moore K.W. de Waal Malefyt R. Coffman R.L. O'Garra A. Annu. Rev. Immunol. 2001; 19: 683-765Crossref PubMed Scopus (5322) Google Scholar, 68Dumoutier L. Leemans C. Lejeune D. Kotenko S.V. Renauld J.-C. J. Immunol. 2001; 167: 3545-3549Crossref PubMed Scopus (357) Google Scholar, 69Wang M. Tan Z. Zhang R. Kotenko S.V. Liang P. J. Biol. Chem. 2002; 277: 7341-7347Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 70Fickenscher H. Hor S. Kupers H. Knappe A. Wittmann S. Sticht H. Trends Immunol. 2002; 23: 89-96Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar) as summarized in Table II.Table IISharing of receptor subunits by multiple type II cytokinesShared subunitOther componentsLigandIL-10RβIL-10RαIL-10IL-22RαIL-22IL-20RαIL-20RβIL-19IL-20RβIL-20IL-20RβIL-24IL-20RβIL-20RαIL-19IL-20RαIL-20IL-20RαIL-24IL-22RαIL-20IL-22RαIL-24IL-22RαIL-20RβIL-20IL-20RβIL-24IL-10RβIL-22 Open table in a new tab Type I and type II cytokines exhibit both cytokine pleiotropy and redundancy. There are now multiple cases wherein these cytokines share receptor chains. This can be viewed as cytokine receptor pleiotropy, wherein a single chain such as βc, γc, gp130, LIFRβ, CNTFRα, IL-2Rβ, IL-4Rα, IL-7Rα, IL-13Rα1, IL-10Rβ, IL20Rα, IL-20Rβ, CNTFRα, or IL-22Rα exists as part of more than a single receptor. In addition, there are examples of what can be viewed as possible cytokine receptor redundancy, wherein more than one functional receptor form can exist for a single cytokine. Examples include the intermediate and high affinity forms of the IL-2 receptor, 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 IL-24 receptors. However, whether these represent redundant receptor forms (as appears likely for IL-3) or instead represent two forms of functional receptors that exert distinctive actions (as perhaps is likely for IL-2 wherein the intermediate affinity form is critical on NK cells whereas the high affinity form is essential for the expansion of activated T cells), still requires further investigation. Given how similar many type I cytokines are to each other and the close relatedness of multiple type I cytokine receptor chains, it is possible that co-evolution of the cytokines and their receptor chains is a process that has allowed the emergence of new distinctive cytokine functions. The same idea is also applicable to interferons and the IL-10 family of type II cytokines. As additional data emerges on the three-dimensional structure of various cytokine-receptor complexes, a greater understanding of these systems will emerge. This should clarify the specific structural basis for the ability of cytokines to interact with more than one receptor and the ability of a receptor chain to interact with multiple cytokines.
Referência(s)