nach oben

Arthritis Research & Therapy

Erschienen in:

01.05.2002 | Review

The paradigm of IL-6: from basic science to medicine

verfasst von: Tetsuji Naka, Norihiro Nishimoto, Tadamitsu Kishimoto

Erschienen in: Arthritis Research & Therapy | Sonderheft 3/2002

Einloggen, um Zugang zu erhalten

Chapter summary

IL-6 is a pleiotropic cytokine with a wide range of biological activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Its activities are shared by IL-6-related cytokines such as leukemia inhibitory factor and oncostatin M. The pleiotropy and redundancy of IL-6 functions have been identified by using a unique receptor system comprising two functional proteins: an IL-6 receptor (IL-6R) and gp130, the common signal transducer of cytokines related to IL-6. Signal transduction through gp130 is mediated by two pathways: the JAK–STAT (Janus family tyrosine kinase–signal transducer and activator of transcription) pathway and the Ras mitogen-activated protein kinase pathway. The negative regulators of IL-6 signaling have also been identified, although the physiological roles of the molecules are not yet fully understood. The pathological roles of IL-6 have also been clarified in various disease conditions, such as inflammatory, autoimmune, and malignant diseases. On the basis of the findings, a new therapeutic approach to block the IL-6 signal using humanized anti-IL-6R antibody for rheumatoid arthritis, Castleman's disease, and multiple myeloma has been attempted.

Muraguchi A, Kishimoto T, Miki T, Kuritani T, Kaieda T, Yoshizaki K, Yamamura Y: T cell-replacing factor (TRF)-induced IgG secretion in human B blastoid cell line and demonstration of acceptors for TRF. J Immunol. 1981, 127: 412-416.PubMed

Yoshizaki K, Nakagawa T, Kaieda T, Muraguchi A, Yamamura Y, Kishimoto T: Induction of proliferation and Ig production in human B leukemic cells by anti-immunoglobulins and T cell factors. J Immunol. 1982, 128: 1296-1301.PubMed

Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A, Tsuna-sawa S, Sakiyama F, Matsui H, Takahara Y, Taniguchi T, Kishimoto T: Complementary DNA for a novel human interleukin (BSF-2) that induces B cell lymphocytes to produce immunoglobulin. Nature. 1986, 324: 73-76.PubMed

Zilberstein A, Ruggieri R, Korn JH, Revel M: Structure and expression of cDNA and genes for human interferon-β2, a distinct species inducible by growth-stimulatory cytokines. EMBO J. 1986, 5: 2529-2537.PubMedPubMedCentral

Sehgal PB, Walther Z, Tamm I: Rapid enhancement of b2-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacylglycerols and calcium ionophore A23187. Proc Natl Acad Sci USA. 1987, 84: 3663-3667.PubMedPubMedCentral

Haegeman G, Content J, Volckaert G, Derynck R, Taverneir J, Fires W: Structural analysis of the sequence encoding for an inducible 26-kDa protein in human fibroblasts. Eur J Biochem. 1986, 159: 625-632.PubMed

Van Damme J, Opdenakker G, Simpson RJ, Rubira MR, Cayphas S, Vink A, Billiau A, Van Snick JV: Identification of the human 26-kDa protein, interferon β2 (IFN-β2), as a B cell hybridoma/ plasmacytoma growth factor induced by interleukin-1 and tumor necrosis factor. J Exp Med. 1987, 165: 914-919.PubMed

Nordan RP, Pumphrey JG, Rudikoff S: Purification and NH2-terminal sequence of a plasmacytoma growth factor derived from the murine macrophage cell line P388D1. J Immunol. 1987, 139: 813-817.PubMed

Uyttenhove C, Coulie PG, Van Snick JV: T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor. J Exp Med. 1988, 167: 1417-1427.PubMed

10.

Van Snick JV, Cayphas S, Szikora J-P, Renauld J-C, Van Roost E, Boon T, Simpson RJ: cDNA cloning of murine interleukin-HP1: homology with human interleukin 6. Eur J Immunol. 1988, 18: 193-197.PubMed

11.

Andus T, Geiger T, Hirano T, Northoff H, Ganter U, Bauer J, Kishimoto T, Heinrich PC: Recombinant human B cell stimulatory factor 2 (BSF-2/ IFNβ2) regulates β-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 1987, 221: 18-22. 10.1016/0014-5793(87)80344-7.PubMed

12.

Gauldie J, Richards C, Harnish D, Landsdorp P, Baumann H: Interferon-β2/ B cell-stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA. 1987, 84: 7251-7255.PubMedPubMedCentral

13.

Castell JV, Gomez-Lechon MJ, David M, Hirano T, Kishimoto T, Heinrich PC: Recombinant human interleukin-6 (IL-6/BSF-2/ HSF) regulates the synthesis of acute phase proteins in human hepatocytes. FEBS Lett. 1988, 232: 347-350. 10.1016/0014-5793(88)80766-X.PubMed

14.

Kishimoto T, Akira S, Narazaki M, Taga T: Interleukin-6 family of cytokines and gp130. Blood. 1995, 86: 1243-1254.PubMed

15.

Noma T, Mizuta T, Rosen A, Hirano T, Kishimoto T, Honjo T: Enhancement of the interleukin-2 receptor expression on T cells by multiple B-lymphotropic lymphokines. Immunol Lett. 1987, 15: 249-253. 10.1016/0165-2478(87)90032-0.PubMed

16.

Okada M, Kitahara M, Kishimoto S, Matsuda T, Hirano T, Kishimoto T: BSF-2/IL-6 functions as killer helper factor in the in vitro induction of cytotoxic T cells. J Immunol. 1988, 141: 1543-1549.PubMed

17.

Ceuppens JL, Baroja ML, Lorre K, Van Damme J, Billiau A: Human T cell activation with phytohemagglutinin: the function of IL-6 as an accessory signal. J Immunol. 1988, 141: 3868-3874.PubMed

18.

Le J, Fredrickson G, Reis L, Diamantsein T, Hirano T, Kishimoto T, Vilcek J: Interleukin-2-dependent and interleukin-2-independent pathways of regulation of thymocyte function by interleukin-6. Proc Natl Acad Sci USA. 1988, 85: 8643-8647.PubMedPubMedCentral

19.

Lotz M, Jirik F, Kabouridis R, Tsoukas C, Hirano T, Kishimoto T, Carson DA: BSF-2/IL-6 is costimulant for human thymocytes and T lymphocytes. J Exp Med. 1988, 167: 1253-1258.PubMed

20.

Garman RD, Jacobs KA, Clark SC, Raulet DH: B cell-stimulatory factor 2 (β2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci USA. 1987, 84: 7629-7633.PubMedPubMedCentral

21.

Ikebuchi K, Wong GG, Clark. SC, Ihle JN, Hirai Y, Ogawa M: Interleukin-6 enhancement of interleukin-3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci USA. 1987, 84: 9035-9039.PubMedPubMedCentral

22.

Koike K, Nakahata T, Takagi M, Kobayashi T, Ishiguro A, Tsujii K, Naganuma K, Okano A, Akiyama Y, Akabane T: Synergism of BSF2/interleukin-6 and interleukin-3 on development of multipotential hemopoietic progenitors in serum free culture. J Exp Med. 1988, 168: 879-890.PubMed

23.

Leary A, Ikebuchi K, Hirai Y, Wong G, Yang Y-C, Clark SC, Ogawa M: Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1a. Blood. 1988, 71: 1759-1763.PubMed

24.

Ogawa M: Differentiation and proliferation of hematopoietic stem cells. Blood. 1993, 81: 2844-2853.PubMed

25.

Stanley ER, Bartocci A, Patinkin D, Rosendaal M, Bradley TR: Regulation of very primitive, multipotent, hemopoietic cells by hemopoietin-1. Cell. 1986, 45: 667-674.PubMed

26.

Nicola NA, Metcalf D, Matsumoto M, Johnson GR: Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem. 1983, 258: 9017-9023.PubMed

27.

Ishibashi T, Kimura H, Uchida T, Kariyone S, Friese P, Burstein SA: Human interleukin6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA. 1987, 86: 5953-5957.

28.

Ishibashi T, Kimura H, Shikama Y, Uchida T, Kariyone S, Hirano T, Kishimoto T, Takatsuki F, Akiyama Y: Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood. 1989, 74: 1241-1244.PubMed

29.

Koike K, Nakahata T, Kubo T, Kikuchi T, Takagi M, Ishiguro A, Tsuji K, Naganuma K, Okano A, Akiyama Y, Akabane T: Interleukin-6 enhances murine megakariocytopoiesis in serum-free culture. Blood. 1990, 75: 2286-2291.PubMed

30.

Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, Koishihara Y, Ohsugi Y, Kumaki K, Taga T, Kishimoto T, Suda T: Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci USA. 1993, 90: 11924-11928.PubMedPubMedCentral

31.

Ulich TR, del Castillo J, Guo KZ: In vivo hematologic effects of recombinant interleukin-6 on hematopoiesis and circulating numbers of RBCs and WBCs. Blood. 1989, 73: 108-110.PubMed

32.

Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H, Fujii Y, Dohi K, Ishikawa H, Ohmoto Y, Yoshizaki K, Hirano T, Kishimoto T: Involvement of interleukin-6 in mesangial proliferation of glomerulonephritis. J Immunol. 1989, 143: 3949-3955.PubMed

33.

Grossman RM, Krueger J, Yourish D, Granelli-Piperno A, Murphy DP, May LT, Kupper TS, Sehgal PB, Gottlieb AB: Interleukin 6 is expressed in high levels in psoriasis skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci USA. 1989, 86: 6367-6371.PubMedPubMedCentral

34.

Yoshizaki K, Nishimoto N, Matsumoto K, Tagoh H, Taga T, Deguchi Y, Kuritani T, Hirano T, Kishimoto T: Interleukin-6 and its receptor expression on the epidermal keratinocytes. Cytokine. 1990, 2: 381-387.PubMed

35.

Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T: Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988, 332: 83-85. 10.1038/332083a0.PubMed

36.

Miki S, Iwano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, Sonoda T, Hirano T, Kishimoto T: Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett. 1989, 250: 607-610. 10.1016/0014-5793(89)80805-1.PubMed

37.

Yamasaki K, Taga T, Hirata Y, Yawata H, Kawanishi Y, Seed B, Taniguchi T, Hirano T, Kishimoto T: Cloning and expression of the human interleukin-6 (BSF-2/INF b2) receptor. Science. 1988, 241: 825-828.PubMed

38.

Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T: Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989, 58: 573-581.PubMed

39.

Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T: Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990, 63: 1149-1157.PubMed

40.

Miyaura C, Onozaki K, Akiyama Y, Taniyama T, Hirano T, Kishimoto T, Suda T: Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (M1). FEBS Lett. 1988, 234: 17-21. 10.1016/0014-5793(88)81293-6.PubMed

41.

Shabo Y, Lotem J, Rubinstein M, Revel M, Clark SC, Wolf SF, Kamen R, Sachs L: The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. Blood. 1988, 72: 2070-2073.PubMed

42.

Metcalf D: Actions and interactions of G-CSF, LIF, and IL-6 on normal and leukemic murine cells. Leukemia. 1989, 3: 349-355.PubMed

43.

Rose TM, Bruce AG: Oncostatin M is a member of a cytokine family which includes leukemia inhibitory factor, granulocyte colony-stimulatory factor and interleukin-6. Proc Natl Acad Sci USA. 1991, 88: 8641-8645.PubMedPubMedCentral

44.

Baumann H, Onorato V, Gauldie J, Jahreis GP: Distinct sets of acute phase plasma proteins are stimulated by separate human hepatocyte-stimulating factors and monokines in rat hepatoma cells. J Biol Chem. 1987, 262: 9756-9768.PubMed

45.

Baumann H, Wong GG: Hepatocyte-stimulatory factor III shares structural and functional identity with leukemia inhibitory factor. J Immunol. 1989, 143: 1163-1167.PubMed

46.

Richards CD, Brown TJ, Shoyab M, Baumann H, Gauldie J: Recombinant oncostatin M stimulates the production of acute phase protein in HepG2 cells and rat primary hepatocytes in vitro. J Immunol. 1992, 148: 1731-1736.PubMed

47.

Miyajima A, Kitamura T, Harada N, Yokota T, Arai K: Cytokine receptors and signal transduction. Annu Rev Immunol. 1992, 10: 295-331. 10.1146/annurev.iy.10.040192.001455.PubMed

48.

Hirano T, Matsuda T, Nakajima K: Signal transduction through gp130 that is shared among the receptors for the interleukin 6 related cytokine subfamily. Stem Cells. 1994, 12: 262-277.PubMed

49.

Hibi M, Nakajima K, Hirano H: IL-6 cytokine family and signal transduction: a model of the cytokine system. J Mol Med. 1996, 74: 1-12.PubMed

50.

Hirota H, Yoshida K, Kishimoto T, Taga T: Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci USA. 1995, 92: 4862-4866.PubMedPubMedCentral

51.

Darnell JE, Kerr IM, Stark GR: Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994, 264: 1415-1421.PubMed

52.

Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Thierfelder WE, Kreider B, Silvennoinen O: Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem Sci. 1994, 19: 222-227. 10.1016/0968-0004(94)90026-4.PubMed

53.

Schindler C, Darnell JE: Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem. 1995, 64: 621-651. 10.1146/annurev.bi.64.070195.003201.PubMed

54.

Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T: Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994, 77: 63-71.PubMed

55.

Guschin D, Rogers N, Briscoe J, Witthuhn BA, Wathing D, Horn F, Pellegrini S, Yasukawa K, Heinrich P, Stark GR, Ihle JN, Kerr IM: A major role for the protein kinase JAK1 in the JAK/STAT signal transduction pathway in response to the interleukin-6. EMBO J. 1995, 14: 1421-1429.PubMedPubMedCentral

56.

Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T: A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990, 9: 1897-1906.PubMedPubMedCentral

57.

Poli V, Mancini FP, Cortese R: IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell. 1990, 63: 643-653.PubMed

58.

Cao Z, Umkek RM, McKnight SL: Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991, 5: 1538-1552.PubMed

59.

De Groot RP, Auwerx J, Karperien M, Staels B, Kruijer W: Activation of junB by PKC and PKA signal transduction through a novel cis-acting element. Nucleic Acids Res. 1991, 19: 775-781.PubMedPubMedCentral

60.

Wegenka UM, Buschmann J, Lutticken C, Heinrich PC, Horn F: Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol Cell Biol. 1993, 13: 276-288.PubMedPubMedCentral

61.

Zhong Z, Wen Z, Darnell JE: Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994, 264: 95-98.PubMed

62.

Fukunaga R, Ishizaka Ikeda E, Pan CX, Seto Y, Nagata S: Functional domains of the granulocyte colony-stimulating factor receptor. EMBO J. 1991, 10: 2855-2865.PubMedPubMedCentral

63.

Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi M, Taga T, Kishimoto T: Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci USA. 1991, 88: 11349-11353.PubMedPubMedCentral

64.

Narazaki M, Witthuhn BA, Yoshida K, Silvennoinen O, Yasukawa K, Ihle JN, Kishimoto T, Taga T: Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc Natl Acad Sci USA. 1994, 91: 2285-2289.PubMedPubMedCentral

65.

Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JJ, Yan-copoulos GD: Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995, 267: 1349-1353.PubMed

66.

Yamanaka Y, Nakajima K, Fukada T, Hibi M, Hirano T: Differentiation and growth arrest signals are generated through the cytoplamic region of gp130 that is essential for Stat3 activation. EMBO J. 1996, 15: 1557-1565.PubMedPubMedCentral

67.

Minami M, Inoue M, Wei S, Takeda K, Matsumoto M, Kishimoto T, Akira S: STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc Natl Acad Sci USA. 1996, 93: 3963-3966. 10.1073/pnas.93.9.3963.PubMedPubMedCentral

68.

Nakajima K, Yamanaka Y, Nakae K, Kojima H, Kiuchi N, Ichiba M, Kitaoka T, Fukada T, Hibi M, Hirano T: A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J. 1996, 15: 3651-3658.PubMedPubMedCentral

69.

Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fijitani Y, Yamaguchi T, Nakajima K, Hirano T: Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity. 1996, 5: 449-460.PubMed

70.

Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S: Stat3 activation is irresponsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol. 1998, 161: 4652-4660.PubMed

71.

Kumar G, Gupta S, Wang S, Nel AE: Involvement of Janus kinases, p52shc, Raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth-responsive B cell line. J Immunol. 1994, 153: 4436-4447.PubMed

72.

Ernst M, Gearing DP, Dunn AR: Functional and biochemical association of Hck with the LIF/IL-6 receptor signal transduct-ing subunit gp130 in embryonic stem cells. EMBO J. 1994, 13: 1574-1584.PubMedPubMedCentral

73.

Matsuda T, Fukada T, Takahashi-Tezuka M, Okuyama Y, Fujitani Y, Hanazono Y, Hirai H, Hirano T: Association and activation of Btk and Tec tyrosine kinases by gp130, a signal transducer of the interleukin-6 family of cytokines. J Biol Chem. 1995, 270: 11037-11039. 10.1074/jbc.270.19.11037.PubMed

74.

Taniguchi T: Cytokine signaling through nonreceptor protein tyrosine kinase. Science. 1995, 268: 251-255.PubMed

75.

Ohtani T, Ishihara K, Atsumi T, Nishida K, Kaneko Y, Miyata H, Itoh T, Narimatsu M, Maeda H, Fukada T, Itoh M, Okano H, Hibi M, Hirano T: Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses. Immunity. 2000, 12: 95-105.PubMed

76.

Ernst M, Inglese M, Waring P, Cambell IK, Bao S, Clay FJ, Alexander WS, Wicks IP, Tarlinton DM, Novak U, Heath JK, Dunn AR: Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med. 2001, 194: 189-203. 10.1084/jem.194.2.189.PubMedPubMedCentral

77.

Starr R, Willson TA, Viney EM, Murray LJL, Rayner JR, Jenkis BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ: A family of cytokine-inducible inhibitors of signaling. Nature. 1997, 387: 917-921. 10.1038/43206.PubMed

78.

Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T: Structure and function of a new STAT-induced STAT inhibitor. Nature. 1997, 387: 924-929. 10.1038/43219.PubMed

79.

Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A: A new protein containing an SH2 domain that inhibits JAK kinase. Nature. 1997, 387: 921-924. 10.1038/43213.PubMed

80.

Minamoto S, Ikegame K, Ueno K, Narazaki M, Naka T, Yamamoto H, Matsumoto T, Saito H, Hosoe S, Kishimoto T: Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. Biochem Biophys Res Commun. 1997, 237: 79-83. 10.1006/bbrc.1997.7080.PubMed

81.

Masuhara M, Sakamoto H, Matsumoto A, Suzuki R, Yasukawa H, Mitsui K, Wakioka T, Tanimura S, Sasaki A, Misawa H, Yokouchi M, Ohtsubo M, Yoshimura A: Cloning and characterization of novel CIS family genes. Biochem Biophys Res Commun. 1997, 239: 436-446. 10.1006/bbrc.1997.7484.

82.

Hilton DJ, Richardson RT, Alexander WS, Viney EM, Sprigg NS, Nicholson SE, Metcalf D, Nicola NA: Twenty proteins containing C-terminal SOCS-box form five structural classes. Proc Natl Acad Sci USA. 1998, 95: 114-119. 10.1073/pnas.95.1.114.PubMedPubMedCentral

83.

Naka T, Fujimoto M, Kishimoto T: Negative regulation of cytokine signaling: STAT-induced STAT inhibitor. Trends Biochem Sci. 1999, 24: 394-398. 10.1016/S0968-0004(99)01454-1.PubMed

84.

Yasukawa H, Sasaki A, Yoshimura A: Negative regulation of cytokine signaling pathways. Annu Rev Immunol. 2000, 18: 143-164. 10.1146/annurev.immunol.18.1.143.PubMed

85.

Krebs DL, Hilton DJ: SOCS proteins: negative regulators of cytokine signaling. Stem Cells. 2001, 19: 378-387.PubMed

86.

Nicholson SE, Willson TA, Farley A, Starr R, Zhang JG, Baca M, Alexander WS, Metcalf D, Hilton DJ, Nicola NA: Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J. 1999, 18: 375-385. 10.1093/emboj/18.2.375.PubMedPubMedCentral

87.

Schmitz J, Weissenbach M, Haan S, Heinrich PC, Schaper F: SOCS-3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP-2 recruitment site of gp130. J Biol Chem. 2000, 275: 12848-12856. 10.1074/jbc.275.17.12848.PubMed

88.

Metcalf D, Greenhalgh CJ, Viney E, Willson TA, Starr R, Nicola NA, Hilton DJ, Alexander WS: Giantism in mice lacking suppressor of cytokine signal-2. Nature. 2000, 405: 1069-1074. 10.1038/35016611.PubMed

89.

Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Nakajima H, Pendeville H, Yasukawa H, Sasaki A, Yoshimura A, Ihle JN: SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell. 1999, 98: 617-627.PubMed

90.

Robert AW, Robb L, Rakar S, Hartley L, Nicola NA, Metcalf D, Hilton DJ, Alexander WS: Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc Natl Acad Sci USA. 2001, 98: 9324-9329. 10.1073/pnas.161271798.

91.

Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola NA, Hilton DJ, Alexander WS: Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc Natl Acad Sci USA. 1998, 95: 14395-14399. 10.1073/pnas.95.24.14395.PubMedPubMedCentral

92.

Naka T, Matsumoto T, Narazaki M, Fujimoto M, Morita Y, Ohsawa Y, Saito H, Nagasawa T, Uchiyama Y, Kishimoto T: Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1(STAT-induced STAT inhibitor) deficient mice. Proc Natl Acad Sci USA. 1998, 95: 15575-15582. 10.1073/pnas.95.26.15577.

93.

Alexander WA, Starr R, Fenner JE, Scott CL, Handman E, Springg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TWH, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ: SOCS1 is critical inhibitor of interferon γ signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell. 1999, 98: 597-608.PubMed

94.

Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN: SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell. 1999, 98: 609-616.PubMed

95.

Morita Y, Naka T, Kawazoe Y, Fujimoto M, Narazaki M, Nakagawa R, Fukuyama H, Nagata S, Kishimoto T: SSI/SOCS-1 suppresses TNF α-induced cell death by regulation of p38 MAP kinase signal in fibroblast. Proc Natl Acad Sci USA. 2000, 97: 5405-5410. 10.1073/pnas.090084797.PubMedPubMedCentral

96.

Kawazoe Y, Naka T, Fujimoto M, Kohzaki H, Morita Y, Narazaki M, Okumura K, Saitoh H, Nakagawa R, Uchiyama Y, Akira S, Kishimoto T: SSI-1/SOCS-1 family proteins inhibit insulin signal transduction pathway through modulating IRS-1 phosphorylation. J Exp Med. 2001, 193: 263-269. 10.1084/jem.193.2.263.PubMedPubMedCentral

97.

Naka T, Tsutsui H, Fujimoto M, Kawazoe Y, Kohzaki H, Morita Y, Nakagawa R, Narazaki M, Adachi K, Yoshimoto T, Nakanishi K, Kishimoto T: SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-γ and IL-4 signaling in vivo. Immunity. 2001, 14: 535-545. 10.1016/S1074-7613(01)00132-7.PubMed

98.

Chung CD, Liao J, Lui B, Rao X, Jay P, Berta P, Shuai K: Specific inhibiton of Stat3 signal transduction by PIAS3. Science. 1997, 278: 1803-1805. 10.1126/science.278.5344.1803.PubMed

99.

Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K: Inhibition of Stat-1 mediated gene activation by PIAS1. Proc Natl Acad Sci USA. 1998, 95: 10626-10631. 10.1073/pnas.95.18.10626.PubMedPubMedCentral

100.

Feldmann M, Elliott MJ, Woody JN, Maini RN: Anti-tumor necrosis factor-α therapy of rheumatoid arthritis. Adv Immunol. 1997, 64: 283-350.PubMed

101.

Yoshizaki K, Nishimoto N, Mihara M, Kishimoto T: Therapy of RA by blocking IL-6 signal transduction with humanized anti-IL-6 receptor antibody. Springer Semin Immunopathol. 1998, 20: 247-259. 10.1007/s002810050033.PubMed

102.

Jilka RH, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boice B, Broxmeyer H, Manolagas SC: Increased osteoclast development after estrogen loss: Mediation by interleukin-6. Science. 1992, 257: 88-91.PubMed

103.

Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, Sato K, Shimizu M, Maini R, Feldman M, Kishimoto T: Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988, 18: 1797-1801.PubMed

104.

Houssiau FA, Devogelaer JP, Van Damme J, De Deuxchaisies CN, Van Snick J: Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritis. Arthritis Rheum. 1988, 31: 784-788.PubMed

105.

Sack U, Kinne R, Marx T, Heppt P, Bender S, Emmrich F: Interleukin-6 in synovial fluid is closely associated with chronic synovitis in rheumatoid arthritis. Rheumatol Int. 1993, 13: 45-51.PubMed

106.

Madhok R, Crilly A, Watson J, Capell HA: Serum interleukin 6 levels in rheumatoid arthritis: correlation with clinical and laboratory indices of disease activity. Ann Rheum Dis. 1993, 52: 232-234.PubMedPubMedCentral

107.

Wendling D, Racadot E, Wijdenes J: Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J Rheumatol. 1993, 20: 259-262.PubMed

108.

Sato K, Tsuchiya M, Saldanha J, Koishihara Y, Ohsugi Y, Kishimoto T, Bendig MM: Reshaping a human antibody to inhibit the interleukin-6-dependent tumor cell growth. Cancer Res. 1993, 53: 851-856.PubMed

109.

Nishimoto N, Sasai M, Shima Y, Nakagawa M, Matsumoto T, Shirai T, Kishimoto T, Yoshizaki Y: Improvement in Castleman's disease by humanized anti-IL-6 receptor antibody therapy. Blood. 2000, 95: 56-61.PubMed

110.

Nishimoto N, Maeda K, Kuritani T, Deguchi H, Sato B, Imai N, Kakehi T, Suemura M, Kishimoto T, Yoshizaki K: Safety and efficacy of repetitive treatment with humanized anti-interleukin-6 receptor antibody (MRA) in rheumatoid arthritis (RA) [abstract]. Arthritis Rheum. 2001, 44: S84-

111.

Mihara M, Kotoh M, Nishimoto N, Oda Y, Kumagai E, Takagi N, Tsunemi K, Ohsugi Y, Kishimoto T, Yoshizaki Y, Takeda Y: Humanized antibody to human interleukin-6 receptor inhibits the development of collagen arthritis in cynomolgus monkeys. Clin Immunol. 2001, 98: 319-326. 10.1006/clim.2000.4989.PubMed

112.

Choy EH, Isenberg DA, Farrow S, Garrood T, Ioannou Y, Bird H, Cheung N, Williams BD, Hazlemau B, Price R, Kishimoto T, Panayi GS: A double-blind, randomized, placebo-controlled trial of anti-interleukin-6 (IL-6) receptor monoclonal antibody in rheumatoid arthritis (RA) [abstract]. Arthritis Rheum. 2001, 44: S84-10.1002/1529-0131(200109)44:9<1993::AID-ART347>3.0.CO;2-A.

113.

Nishimoto N, Ogata A, Shima Y, Tani Y, Ogawa H, Nakagawa M, Sugiyama H, Yoshizaki K, Kishimoto T: Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130 [abstract]. J Exp Med. 1994, 179: 1343-1347.PubMed

Titel: The paradigm of IL-6: from basic science to medicine
verfasst von: Tetsuji Naka
Norihiro Nishimoto
Tadamitsu Kishimoto
Publikationsdatum: 01.05.2002
Verlag: BioMed Central
Erschienen in: Arthritis Research & Therapy / Ausgabe Sonderheft 3/2002
Elektronische ISSN: 1478-6362
DOI: https://doi.org/10.1186/ar565

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

19.04.2024 | Vorhofflimmern | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

The paradigm of IL-6: from basic science to medicine

Chapter summary

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Denken Sie bei starker Blutung auch an die Hemmkörper-Hämophilie

Update Innere Medizin

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Chapter summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Sonderheft 3/2002

Is juvenile rheumatoid arthritis/juvenile idiopathic arthritis different from rheumatoid arthritis?

Engineering of tissue inhibitor of metalloproteinases mutants as potential therapeutics

Tissue engineering: chondrocytes and cartilage

VEGF and imaging of vessels in rheumatoid arthritis

Single nucleotide polymorphisms and disease gene mapping

Humanized mice as a model for rheumatoid arthritis

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Denken Sie bei starker Blutung auch an die Hemmkörper-Hämophilie

Update Innere Medizin