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A role for IL-27p28 as an antagonist of gp130-mediated signaling

Nature Immunology volume 11, pages 1119–1126 (2010)Cite this article

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Abstract

The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit of its receptor, combined with gp130, a common receptor chain used by several cytokines, including IL-6. Notably, the IL-27 subunits p28 (IL-27p28) and EBI3 are not always expressed together, which suggests that they may have unique functions. Here we show that IL-27p28, independently of EBI3, antagonized cytokine signaling through gp130 and IL-6-mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. Mice transgenic for expression of IL-27p28 showed a substantial defect in the formation of germinal centers and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.

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Figure 1: IL-27p28 has biological activity in the absence of EBI3.
Figure 2: IL-27p28 antagonizes gp130-mediated STAT phosphorylation.
Figure 3: Phenotypic analysis of p28-transgenic mice.
Figure 4: Transgenic overexpression of IL-27p28 antagonizes the activity of IL-6 and IL-27 on CD4+ T cells.
Figure 5: Failure of p28-transgenic mice to generate an antigen-specific IgG response after immunization with a thymus-dependent antigen.
Figure 6: Transgenic expression of IL-27p28 blocks the formation of GC reactions after immunization with a thymus-dependent antigen.

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  • 21 January 2011

    In the version of this article initially published, the author name M. Merle Elloso and the associated affiliation were incorrect. The correct affiliation is Centocor Research and Development, Inc. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Kastelein, R.A., Hunter, C.A. & Cua, D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Damsker, J.M., Hansen, A.M. & Caspi, R.R. Th1 and Th17 cells: adversaries and collaborators. Ann. NY Acad. Sci. 1183, 211–221 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Jones, S.A. Directing transition from innate to acquired immunity: defining a role for IL-6. J. Immunol. 175, 3463–3468 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Jones, S.A., Richards, P.J., Scheller, J. & Rose-John, S. IL-6 transsignaling: the in vivo consequences. J. Interferon Cytokine Res. 25, 241–253 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Ding, C., Cicuttini, F., Li, J. & Jones, G. Targeting IL-6 in the treatment of inflammatory and autoimmune diseases. Expert Opin. Investig. Drugs 18, 1457–1466 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Benigni, F. et al. Six different cytokines that share GP130 as a receptor subunit, induce serum amyloid A and potentiate the induction of interleukin-6 and the activation of the hypothalamus-pituitary-adrenal axis by interleukin-1. Blood 87, 1851–1854 (1996).

    CAS  PubMed  Google Scholar 

  7. Hangoc, G. et al. In vivo effects of recombinant interleukin-11 on myelopoiesis in mice. Blood 81, 965–972 (1993).

    CAS  PubMed  Google Scholar 

  8. Metcalf, D., Nicola, N.A. & Gearing, D.P. Effects of injected leukemia inhibitory factor on hematopoietic and other tissues in mice. Blood 76, 50–56 (1990).

    CAS  PubMed  Google Scholar 

  9. Muraguchi, A. et al. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J. Exp. Med. 167, 332–344 (1988).

    Article  CAS  PubMed  Google Scholar 

  10. Muraguchi, A. et al. T cell-replacing factor- (TRF) induced IgG secretion in a human B blastoid cell line and demonstration of acceptors for TRF. J. Immunol. 127, 412–416 (1981).

    CAS  PubMed  Google Scholar 

  11. Senaldi, G. et al. Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family. Proc. Natl. Acad. Sci. USA 96, 11458–11463 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Larousserie, F. et al. Differential effects of IL-27 on human B cell subsets. J. Immunol. 176, 5890–5897 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Pflanz, S. et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172, 2225–2231 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Heinzel, F.P., Hujer, A.M., Ahmed, F.N. & Rerko, R.M. In vivo production and function of IL-12 p40 homodimers. J. Immunol. 158, 4381–4388 (1997).

    CAS  PubMed  Google Scholar 

  16. Batten, M. & Ghilardi, N. The biology and therapeutic potential of interleukin 27. J. Mol. Med. 85, 661–672 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Devergne, O. et al. A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes. J. Virol. 70, 1143–1153 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Maaser, C., Egan, L.J., Birkenbach, M.P., Eckmann, L. & Kagnoff, M.F. Expression of Epstein-Barr virus-induced gene 3 and other interleukin-12-related molecules by human intestinal epithelium. Immunology 112, 437–445 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sonobe, Y. et al. Production of IL-27 and other IL-12 family cytokines by microglia and their subpopulations. Brain Res. 1040, 202–207 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Collison, L.W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Niedbala, W. et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur. J. Immunol. 37, 3021–3029 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Devergne, O., Birkenbach, M. & Kieff, E. Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc. Natl. Acad. Sci. USA 94, 12041–12046 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stumhofer, J.S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Kumanogoh, A. et al. Impairment of antigen-specific antibody production in transgenic mice expressing a dominant-negative form of gp130. Proc. Natl. Acad. Sci. USA 94, 2478–2482 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Senaldi, G. et al. Regulatory effects of novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) on B cell function. J. Immunol. 168, 5690–5698 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Takatsuki, F. et al. Human recombinant IL-6/B cell stimulatory factor 2 augments murine antigen-specific antibody responses in vitro and in vivo. J. Immunol. 141, 3072–3077 (1988).

    CAS  PubMed  Google Scholar 

  27. Nurieva, R.I. et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138–149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shimozato, O. et al. The secreted form of p28 subunit of interleukin (IL)-27 inhibits biological functions of IL-27 and suppresses anti-allogeneic immune responses. Immunology 128, e816–e825 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Liu, J., Guan, X. & Ma, X. Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-γ-mediated pathways. J. Exp. Med. 204, 141–152 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Molle, C. et al. IL-27 synthesis induced by TLR ligation critically depends on IFN regulatory factor 3. J. Immunol. 178, 7607–7615 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Stumhofer, J.S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. McGeachy, M.J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Fischer, M. et al. I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat. Biotechnol. 15, 142–145 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Timmermann, A. et al. Different epitopes are required for gp130 activation by interleukin-6, oncostatin M and leukemia inhibitory factor. FEBS Lett. 468, 120–124 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Iritani, B.M., Forbush, K.A., Farrar, M.A. & Perlmutter, R.M. Control of B cell development by Ras-mediated activation of Raf. EMBO J. 16, 7019–7031 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jack, R.S., Imanishi-Kari, T. & Rajewsky, K. Idiotypic analysis of the response of C57BL/6 mice to the (4-hydroxy-3-nitrophenyl)acetyl group. Eur. J. Immunol. 7, 559–565 (1977).

    Article  CAS  PubMed  Google Scholar 

  37. Arend, W.P., Palmer, G. & Gabay, C. IL-1, IL-18, and IL-33 families of cytokines. Immunol. Rev. 223, 20–38 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Mentink-Kane, M.M. et al. IL-13 receptor α2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc. Natl. Acad. Sci. USA 101, 586–590 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Crabe, S. et al. The IL-27 p28 subunit binds cytokine-like factor 1 to form a cytokine regulating NK and T cell activities requiring IL-6R for signaling. J. Immunol. 183, 7692–7702 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Scheller, J., Schuster, B., Holscher, C., Yoshimoto, T. & Rose-John, S. No inhibition of IL-27 signaling by soluble gp130. Biochem. Biophys. Res. Commun. 326, 724–728 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Hibi, M. et al. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63, 1149–1157 (1990).

    Article  CAS  PubMed  Google Scholar 

  42. Brakenhoff, J.P., Bos, H.K., Grotzinger, J., Rose-John, S. & Aarden, L.A. Identification of residues in the putative 5th helical region of human interleukin-6, important for activation of the IL-6 signal transducer, gp130. FEBS Lett. 395, 235–240 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Schroers, A. et al. Dynamics of the gp130 cytokine complex: a model for assembly on the cellular membrane. Protein Sci. 14, 783–790 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kopf, M. et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368, 339–342 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Wu, Y. et al. IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation. Int. Immunol. 21, 745–756 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fattori, E. et al. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood 83, 2570–2579 (1994).

    CAS  PubMed  Google Scholar 

  47. Shen, M.M. et al. Expression of LIF in transgenic mice results in altered thymic epithelium and apparent interconversion of thymic and lymph node morphologies. EMBO J. 13, 1375–1385 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chae, S.C. et al. Identification of polymorphisms in human interleukin-27 and their association with asthma in a Korean population. J. Hum. Genet. 52, 355–361 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Imielinski, M. et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41, 1335–1340 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li, C.S. et al. Interleukin-27 polymorphisms are associated with inflammatory bowel diseases in a Korean population. J. Gastroenterol. Hepatol. 24, 1692–1696 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. O'Shea, J. J. Targeting the Jak/STAT pathway for immunosuppression. Ann. Rheum. Dis. 63, ii67–ii71 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. O'Shea, J.J., Pesu, M., Borie, D.C. & Changelian, P.S. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat. Rev. Drug Discov. 3, 555–564 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Howlett, M., Menheniott, T.R., Judd, L.M. & Giraud, A.S. Cytokine signalling via gp130 in gastric cancer. Biochim. Biophys. Acta 1793, 1623–1633 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hogan, B., Beddington, R. Costantini, F. & Lacy, E. Manipulating the Mouse Embryo 2nd edn. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA, 1994).

  56. Vriend, G. WHAT IF: a molecular modeling and drug design program. J. Mol. Graph. 8, 52–56 (1990).

    Article  CAS  PubMed  Google Scholar 

  57. Carson, M. Ribbons. Methods Enzymol. 277, 493–505 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Allman, D.M., Ferguson, S.E., Lentz, V.M. & Cancro, M.P. Peripheral B cell maturation. II. Heat-stable antigen(hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells. J. Immunol. 151, 4431–4444 (1993).

    CAS  PubMed  Google Scholar 

  59. Scholz, J.L. et al. BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact. Proc. Natl. Acad. Sci. USA 105, 15517–15522 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank D. Gorman for generating the IL-27 and IL-27p28 minicircles. Supported by the US National Institutes for Health (AI-042334 to C.A.H.; AI-054488 to M.P.C.; 1-T32-AI-055428 to J.S.S. and W.J.Q. III; and 2-T32-AI-007532-11 to E.D.T.), the Abramson Cancer Center (Center for Digestive Diseases), the state of Pennsylvania, the Deutsche Forschungsgemeinschaft (Bonn, Germany; SFB415, B5 to S.R-J., and SFB415, B7 to J.G. and B.S.), the Cluster of Excellence 'Inflammation at Interfaces' and the Marie Lowe Cancer Center of the University of Pennsylvania (C.A.H.).

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Author notes

  1. Jason S Stumhofer, Elia D Tait and William J Quinn III: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA

    Jason S Stumhofer, Elia D Tait, Aisling C O'Hara & Christopher A Hunter

  2. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    William J Quinn III, Radhika Goenka & Michael P Cancro

  3. Department of Immunology, ZymoGenetics, Seattle, Washington, USA

    Nancy Hosken & Steven D Levin

  4. Institute for Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany

    Björn Spudy, Stefan Rose-John & Joachim Grötzinger

  5. Cardiff University, School of Medicine, Cardiff, UK

    Ceri A Fielding & Simon A Jones

  6. Merck Research Laboratories, DNAX Discovery Research, Palo Alto, California, USA

    Yi Chen & Daniel J Cua

  7. Shenandoah Biotechnology, Warwick, Pennsylvania, USA

    Michael L Jones

  8. Department of Inflammation Research, Amgen, Thousand Oaks, California, USA

    Christiaan J M Saris

  9. Centocor Research and Development, Inc., Radnor, Pennsylvania, USA

    M Merle Elloso

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  1. Jason S Stumhofer
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Contributions

J.S.S. and C.A.H. contributed to all studies and wrote the manuscript; E.D.T., W.J.Q. III, N.H., M.P.C. and S.D.L. were involved in analyzing p28-transgenic mice; R.G. contributed to studies of GC formation; C.J.M.S. contributed to the studies of Il27ra−/− mice; M.M.E. contributed to studies with Ebi3−/− mice; A.C.O. contributed to studies of intracellular staining for IL-27p28; B.S., S.R.-J. and J.G. did the p28-gp130 modeling and contributed to its analysis; C.A.F. and S.A.J. did the biacore assays and contributed to their analysis; M.L.J. provided the recombinant IL-27p28 protein; and Y.C. and D.J.C. did hydrodynamics-based transfection experiments with minicircle DNA and contributed to their analysis.

Corresponding author

Correspondence to Christopher A Hunter.

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Competing interests

C.A.H. and J.S.S. have a patent application on the use of p28 to limit gp130 signaling. N.H. and S.D.L. are employees of ZymoGenetics; Y.C. and D.J.C. are employees of DNAX Discovery Research; M.L.J. is an employee of Shenandoah Biotechnology; C.J.M.S. is an employee of Amgen; and M.M.E. is an employee of Centocor Research and Development.

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Stumhofer, J., Tait, E., III, W. et al. A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nat Immunol 11, 1119–1126 (2010). https://doi.org/10.1038/ni.1957

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