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Cited by 172Cytokine Signaling Pathways and InteractionsRheumatoid Arthritis Research and TherapiesPsoriasis: Treatment and Pathogenesis

Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir

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HIRANO, Toshio·2010·Proceedings of the Japan Academy, Series B
DOI 10.2183/pjab.86.717PMC PMC3066534
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Abstract

In this review, the author discusses the research that led to the identification and characterization of interleukin 6 (IL-6), including his own experience isolating IL-6, and the roles this cytokine has on autoimmune and inflammatory diseases. The cDNAs encoding B-cell stimulatory factor 2 (BSF-2), interferon (IFN)-beta2 and a 26-kDa protein were independently cloned in 1986, which in turn led to the identification of each. To resolve the confusing nomenclature, these identical molecules were named IL-6. Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases as rheumatoid arthritis (RA).IL-6 activates both the STAT3 and SHP2/Gab/MAPK signaling pathways via the gp130 signal transducer. F759 mice, which contain a single amino-acid substitution in gp130 (Y759F) and show enhanced STAT3 activation, spontaneously develop a RA-like arthritis as they age. F759 arthritis is dependent on CD4(+) T cells, IL-6, and IL-17A, and is enhanced by the pX gene product from human T cell leukemia virus 1 (HTLV-1). Arthritis development in these mice requires that the F759 mutation is present in nonhematopoietic cells, but not in immune cells, highlighting the important role of the interaction between nonimmune tissues and the immune system in this disease. Furthermore, this interaction is mediated by the IL-6 amplifier through STAT3 and NF-kappaB. Ultimately, this model may represent a general etiologic process underlying other autoimmune and inflammatory diseases. More importantly, the understanding of IL-6 has paved the way for new therapeutic approaches for RA and other autoimmune and inflammatory diseases.

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  • Interactions between immune cells and non-immune tissues play critical roles in chronic inflammatory diseases and autoimmune diseases.

    “Consistently, evidence has indicated that interactions between immune cells and non-immune tissues play critical roles in chronic inflammatory diseases and autoimmune diseases (3, 41, 49–51).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [41]

    In “The view from the mountaintop,” the paper says its model implies that interactions between nonimmune and immune systems may play critical roles in autoimmune diseases and chronic inflammatory proliferative disease. The citing sentence presents that tentative, model-based conclusion as an established role across chronic inflammatory diseases more broadly. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Enhancement of IL-6-STAT3 signaling causes IL-17A-dependent autoimmune arthritis in mice.

    “On the other hand, the enhancement of IL-6–STAT3 signaling causes IL-17A-dependent autoimmune arthritis in mice (41, 63, 66).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [41]

  • There is an in vivo positive-feedback amplification loop of IL-6 production via Th17 cell differentiation and their interaction with non-immune cells such as fibroblasts.

    “Therefore, there is an in vivo positive-feedback amplification loop of IL-6 production via Th17 cell differentiation and their interaction with non-immune cells, such as fibroblasts (41).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [41]

  • Amplification of the IL-6-STAT3 axis is augmented by several pathways after the induction of other STAT3 and NF-κB activators during inflammation.

    “Therefore, amplification of the IL-6–STAT3 axis is augmented by several pathways after the induction of other STAT3 and NF-κB activators during inflammation processes (Fig. 3) (41, 66).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [41]

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  1. [2]Ermann J. Fathman C.G. (2001) Autoimmune diseases: genes, bugs and failed regulation. Nat. Immunol. 2, 759– 761 11526377
  2. [3]O’Shea J.J. Ma A. Lipsky P. (2002) Cytokines and autoimmunity. Nat. Rev. Immunol. 2, 37– 45 11905836
  3. [5]Mocci S. Lafferty K. Howard M. (2000) The role of autoantigens in autoimmune disease. Curr. Opin. Immunol. 12, 725– 730 11102779
  4. [6]Skapenko A. Leipe J. Lipsky P.E. Schulze-Koops H. (2005) The role of the T cell in autoimmune inflammation. Arthritis Res. Ther. 7, S4– S14 15833146 PMC2833981
  5. [7]Hirano T. (1998) Interleukin 6 and its receptor: ten years later. Int. Rev. Immunol. 16, 249– 284 9505191
  6. [8]Matsumoto I. Staub A. Benoist C. Mathis D. (1999) Arthritis Provoked by Linked T and B Cell Recognition of a Glycolytic Enzyme. Science 286, 1732– 1735 10576739
  7. [9]Hirano T. (2002) Cytokines in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev. 13, 297– 298 12220544
  8. [11]Hirano T. Matsuda T. Turne M. Miyasaka N. Buchan G. Tang B. (1988) Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur. J. Immunol. 18, 1797– 1801 2462501
  9. [12]Ishihara K. Hirano T. (2002) IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev. 13, 357– 368 12220549
  10. [13]Andreakos E. Foxwell B. Brennan F. Maini R. Feldmann M. (2002) Cytokines and anti-cytokine biologicals in autoimmunity: present and future. Cytokine Growth Factor Rev. 13, 299– 313 12220545
  11. [14]Feldmann M. Brennan F. Maini R. (1996) Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397– 440 8717520
  12. [15]Feldmann M. Maini R.N. (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19, 163– 196 11244034
  13. [16]Nishimoto N. Kishimoto T. Yoshizaki K. (2000) Anti-interleukin 6 receptor antibody treatment in rheumatic disease. Ann. Rheum. Dis. 59, i21– i27 11053081 PMC1766618
  14. [20]Hata H. Sakaguchi N. Yoshitomi H. Iwakura Y. Sekikawa K. Azuma Y. (2004) Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J. Clin. Invest. 114, 582– 588 15314695 PMC503774
  15. [21]Alonzi T. Fattori E. Lazzaro D. Costa P. Probert L. Kollias G. (1998) Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187, 461– 468 9463396 PMC2212160
  16. [22]Ohshima S. Saeki Y. Mima T. Sasai M. Nishioka K. Nomura S. (1998) Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc. Natl. Acad. Sci. USA 95, 8222– 8226 9653168 PMC20957
  17. [23]Murakami M. Kamimura D. Hirano T. (2004) New IL-6 (gp130) family cytokine members, CLC/NNT1/BSF3 and IL-27. Growth Factors 2004, 2 15253382
  18. [24]Kamimura D. Ishihara K. Hirano T. (2003) IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev. Physiol. Biochem. Pharmacol. 149, 1– 38 12687404
  19. [25]Fukada T. Hibi M. Yamanaka Y. Takahashi-Tezuka M. Fujitani Y. Yamaguchi T. (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5, 449– 460 8934572
  20. [26]Ohtani T. Ishihara K. Atsumi T. Nishida K. Kaneko Y. Miyata T. (2000) Dissection of signaling cascades through gp130 in vivo: Reciprocal roles for STAT3- and SHP2-mediated signals in immune responses. Immunity 12, 95– 105 10661409
  21. [28]Harrington L.E. Hatton R.D. Mangan P.R. Turner H. Murphy T.L. Murphy K.M. (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123– 1132 16200070
  22. [29]Park H. Li Z. Yang X.O. Chang S.H. Nurieva R. Wang Y.H. (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133– 1141 16200068 PMC1618871
  23. [32]Mangan P.R. Harrington L.E. O’Quinn D.B. Helms W.S. Bullard D.C. Elson C.O. (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231– 234 16648837
  24. [34]Nishihara M. Ogura H. Ueda N. Tsuruoka M. Kitabayashi C. Tsuji F. (2007) IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int. Immunol. 19, 695– 702 17493959
  25. [35]Linterman M.A. Vinuesa C.G. (2010) Signals that influence T follicular helper cell differentiation and function. Semin. Immunopathol. (in press) 20107805
  26. [37]Schimpl A. Wecker E. (1972) Replacement of T cell function by a T cell product. Nat. New Biol. 235, 15– 17 4503682
  27. [38]Hirano T. Teranishi T. Toba T. Sakaguchi N. Fukukawa T. Tsuyuguchi I. (1981) Human helper T cell factor(s) (ThF). I. Partial purification and characterization. J. Immunol. 126, 517– 522 6161177
  28. [39]Muraguchi A. Kishimoto T. Miki Y. Kuritani T. Kaieda T. Yoshizaki K. (1981) T cell-replacing factor(TRF)-induced IgG secretion in human B blastoid cell line and demonstration of acceptors for TRF. J. Immunol. 127, 412– 416 6972960
  29. [40]Teranishi T. Hirano T. Arima N. Onoue K. (1982) Human helper T cell factor(s) (ThF). II. Induction of IgG production in B lymphoblastoid cell lines and identification of T cell replacing factor (TRF)-like factor(s). J. Immunol. 128, 1903– 1908 6801125
  30. [41]Okada M. Sakaguchi N. Yoshimura N. Hara H. Shimizu K. Yoshida N. (1983) B cell growth factor and B cell differentiation factor from human T hybridomas: Two distinct kinds of BCGFs and their synergism in B cell proliferation. J. Exp. Med. 157, 583– 590 6600487 PMC2186927
  31. [42]Hirano T. Teranishi T. Onoue K. (1984) Human helper T cell factor(s). III. Characterization of B cell differentiation factor I (BCDF I). J. Immunol. 132, 229– 234 6228579
  32. [43]Hirano T. Teranishi T. Lin B. Onoue K. (1984) Human helper T cell factor(s). IV. Demonstration of a human late-acting B cell differentiation factor acting on Staphylococcus aureus Cowan I-stimulated B cells. J. Immunol. 133, 798– 802 6234360
  33. [44]Hirano T. Taga T. Nakano N. Yasukawa K. Kashiwamura S. Shimizu K. (1985) Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc. Natl. Acad. Sci. USA 82, 5490– 5494 2410927 PMC391148
  34. [46]Hirano T. Yasukawa K. Harada H. Taga T. Watanabe Y. Matsuda T. (1986) Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324, 73– 76 3491322
  35. [47]Haegeman G. Content J. Volckaert G. Derynck R. Tavernier J. Fiers W. (1986) Structural analysis of the sequence encoding for an inducible 26-kDa protein in human fibroblasts. Eur. J. Biochem. 159, 625– 632 3758081
  36. [48]Zilberstein A. Ruggieri R. Korn J.H. Revel M. (1986) Structure and expression of cDNA and genes for human interferon-β-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J. 5, 2529– 2537 3023045 PMC1167149
  37. [49]Marx J.L. (1988) Orphan interferon finds a new home. Science 239, 25– 26 3276001
  38. [50]Sehgal P.B. May T.T. Tamm I. Vilcek J. (1987) Human β2 interferon and B-cell differentiation factor BSF-2 are identical. Science 235, 731– 732 3492764
  39. [51]Andus T. Geiger T. Hirano T. Northoff H. Ganter U. Bauer J. (1987) Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-beta 2) regulates β-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 221, 18– 22 3305075
  40. [52]Gauldie J. Richards C. Harnish D. Lansdorp P. Baumann H. (1987) 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 84, 7251– 7255 2444978 PMC299269
  41. [53]Van Damme J. Opdenakker G. Simpson R.J. Rubira M.R. Cayphas S. Vink A. (1987) Dentification of the human 26-kDa protein, interferon β2 (IFNβ2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J. Exp. Med. 165, 914– 919 3493322 PMC2188297
  42. [54]Kawano M. Hirano T. Matsuda T. Taga T. Horii Y. Iwato K. (1988) Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332, 83– 85 3258060
  43. [55]Van Snick J. Cayphas S. Szikora J.P. Renauld J.C. Van Roost E. Boon T. (1988) cDNA cloning of murine interleukin-HP1:homology with human interleukin 6. Eur. J. Immunol. 18, 193– 197 2965020
  44. [56]Sehgal P.B. Grienger G. Tosato G. (eds.) (1989) Regulation of the acute phase and immune responses: Interleukin-6. Ann. New York Acad. Sci. 557, 1– 583 2472086
  45. [57]Noma Y. Sideras P. Naito T. Bergstedt-Lindquist S. Azuma C. Severinson E. (1986) Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature 319, 640– 646 3005865
  46. [58]Kinashi T. Harada N. Severinson E. Tanabe T. Sideras P. Konishi M. (1986) Cloning of complementary DNA encoding T-cell replacing factor and identity with B-cell growth factor II. Nature 324, 70– 73 3024009
  47. [61]Heinrich P.C. Castell J.V. Andus T. (1990) Interleukin-6 and the acute phase response. Biochem. J. 265, 621– 636 1689567 PMC1133681
  48. [62]Yamasaki K. Taga T. Hirata Y. Yawata H. Kawanishi Y. Seed B. (1988) Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science 241, 825– 828 3136546
  49. [63]Hibi M. Murakami M. Saito M. Hirano T. Taga T. Kishimoto T. (1990) Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63, 1149– 1157 2261637
  50. [64]Taga T. Hibi M. Hirata Y. Yamasaki K. Yasukawa K. Matsuda T. (1989) Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58, 573– 581 2788034
  51. [65]Hirano T. (1992) Interleukin-6 and its relation to inflammation and disease. Clin. Immunol. Immunopathol. 62, S60– S65 1728989
  52. [66]Iwakura Y. Tosu M. Yoshida E. Takiguchi M. Sato K. Kitajima I. (1991) Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science 253, 1026– 1028 1887217
  53. [67]Ishihara K. Sawa S. Ikushima H. Hirota S. Atsumi T. Kamimura D. (2004) The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis. Int. Immunol. 16, 455– 465 14978019
  54. [68]Zhu J. Yamane H. Cote-Sierra J. Guo L. Paul W.E. (2006) GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res. 16, 3– 10 16467870
  55. [69]Mosmann T.R. Coffman R.L. (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145– 173 2523712
  56. [70]Glimcher L.H. Murphy K.M. (2000) Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14, 1693– 1711 10898785
  57. [71]Iwakura Y. Ishigame H. (2006) The IL-23/IL-17 axis in inflammation. J. Clin. Invest. 116, 1218– 1222 16670765 PMC1451213
  58. [72]Hirota K. Hashimoto M. Yoshitomi H. Tanaka S. Nomura T. Yamaguchi T. (2007) T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J. Exp. Med. 204, 41– 47 17227914 PMC2118414
  59. [73]Bettelli E. Oukka M. Kuchroo V.K. (2007) TH-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8, 345– 350 17375096
  60. [74]Afzali B. Lombardi G. Lechler R.I. Lord G.M. (2007) The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin. Exp. Immunol. 148, 32– 46 17328715 PMC1868863
  61. [75]Ogura H. Murakami M. Okuyama Y. Tsuruoka M. Kitabayashi C. Kanamoto M. (2008) Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction. Immunity 29, 628– 636 18848474
  62. [76]Sakaguchi S. (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455– 458 10850488

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Authors
HIRANO, T.
Affiliations
Japan Science and Technology Agency (JP)
Corresponding author
HIRANO, Toshio
Venue
Proceedings of the Japan Academy, Series B
Publisher
Japan Academy
Published
2010
Volume
86
Issue
7
Pages
717-730
ISSN
  • 0386-2208 (ISSN-L)
  • 1349-2896
DOI
10.2183/pjab.86.717
PMC
PMC3066534
OpenAlex
W2019466258
Cited by
172
References
12
Citations by year
2026: 2 · 2025: 9 · 2024: 13 · 2023: 19 · 2022: 14 · 2021: 16 · 2020: 13 · 2019: 9 · 2018: 2 · 2017: 5 · 2016: 11 · 2015: 10 · 2014: 11 · 2013: 11 · 2012: 17
FWCI
1.36
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the Japan Academy Series B (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Lunds Universitet
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
interleukin-6, B cell stimulatory factor 2, interferon-beta, rheumatoid arthritis, gp130 signaling, STAT3, IL-17A, CD4+ T cells, NF-κB, autoimmune etiology, rheumatoid arthritis therapy
MeSH terms
Animals, Arthritis, Rheumatoid, Autoimmune Diseases, Humans, Inflammation, Human T-lymphotropic virus 1, Interleukin-6, History, 20th Century

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