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IL-17C regulates the innate immune function of epithelial cells in an autocrine manner

Nature Immunology volume 12, pages 1159–1166 (2011)Cite this article

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Abstract

Interleukin 17C (IL-17C) is a member of the IL-17 family that is selectively induced in epithelia by bacterial challenge and inflammatory stimuli. Here we show that IL-17C functioned in a unique autocrine manner, binding to a receptor complex consisting of the receptors IL-17RA and IL-17RE, which was preferentially expressed on tissue epithelial cells. IL-17C stimulated epithelial inflammatory responses, including the expression of proinflammatory cytokines, chemokines and antimicrobial peptides, which were similar to those induced by IL-17A and IL-17F. However, IL-17C was produced by distinct cellular sources, such as epithelial cells, in contrast to IL-17A, which was produced mainly by leukocytes, especially those of the TH17 subset of helper T cells. Whereas IL-17C promoted inflammation in an imiquimod-induced skin-inflammation model, it exerted protective functions in dextran sodium sulfate–induced colitis. Thus, IL-17C is an essential autocrine cytokine that regulates innate epithelial immune responses.

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Figure 1: The biological effects of IL-17C are mediated through IL-17RA–IL-17RE heterodimeric receptor complexes.
Figure 2: IL-17C induces host-defense pathways in epithelial cells.
Figure 3: IL-17C is expressed by mucosal epithelial cells in response to inflammation.
Figure 4: Many factors independently regulate IL-17C expression.
Figure 5: Leukocytes are not a predominant source of IL-17C in vivo.
Figure 6: IL-17C is expressed during DSS-induced colitis.
Figure 7: Role of the IL-17RE pathway in the recovery of epithelial cells in the DSS-induced colitis model.
Figure 8: Proinflammatory role of the IL-17C pathway in a mouse model of psoriasis.

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References

  1. Abraham, C. & Medzhitov, R. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology 140, 1729–1737 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Nestle, F.O., Di Meglio, P., Qin, J.Z. & Nickoloff, B.J. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679–691 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Saenz, S.A., Taylor, B.C. & Artis, D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol. Rev. 226, 172–190 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sims, J.E. & Smith, D.E. The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 10, 89–102 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Kishimoto, T. IL-6: from its discovery to clinical applications. Int. Immunol. 22, 347–352 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Jager, A. & Kuchroo, V.K. Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation. Scand. J. Immunol. 72, 173–184 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Blaschitz, C. & Raffatellu, M. Th17 cytokines and the gut mucosal barrier. J. Clin. Immunol. 30, 196–203 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kolls, J.K. & Khader, S.A. The role of Th17 cytokines in primary mucosal immunity. Cytokine Growth Factor Rev. 21, 443–448 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ahmed, M. & Gaffen, S.L. IL-17 in obesity and adipogenesis. Cytokine Growth Factor Rev. 21, 449–453 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Iwakura, Y., Ishigame, H., Saijo, S. & Nakae, S. Functional specialization of interleukin-17 family members. Immunity 34, 149–162 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Hymowitz, S.G. et al. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. EMBO J. 20, 5332–5341 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ely, L.K., Fischer, S. & Garcia, K.C. Structural basis of receptor sharing by interleukin 17 cytokines. Nat. Immunol. 10, 1245–1251 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liang, S.C. et al. An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment. J. Immunol. 179, 7791–7799 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Wright, J. F. et al. Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J. Biol. Chem. 282, 13447–13455 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Fort, M.M. et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15, 985–995 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, J. et al. IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J. Biol. Chem. 276, 1660–1664 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Rickel, E.A. et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J. Immunol. 181, 4299–4310 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Shi, Y. et al. A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity. J. Biol. Chem. 275, 19167–19176 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Liu, Y. et al. IL-17A and TNF-α exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J. Immunol. 186, 3197–3205 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Aujla, S.J. et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat. Med. 14, 275–281 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ishigame, H. et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108–119 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Khader, S.A. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat. Immunol. 8, 369–377 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Ogawa, A., Andoh, A., Araki, Y., Bamba, T. & Fujiyama, Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 110, 55–62 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Yang, X. O. et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 205, 1063–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Johansen, C. et al. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br. J. Dermatol. 160, 319–324 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Leipe, J. et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 62, 2876–2885 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Hofstetter, H. H. et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol. 237, 123–130 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010).

    Article  PubMed  Google Scholar 

  31. Lubberts, E. et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 50, 650–659 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Rizzo, H.L. et al. IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J. Immunol. 186, 1495–1502 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Holland, D.B., Bojar, R.A., Farrar, M.D. & Holland, K.T. Differential innate immune responses of a living skin equivalent model colonized by Staphylococcus epidermidis or Staphylococcus aureus. FEMS Microbiol. Lett. 290, 149–155 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Johansen, C., Riis, J.L., Gedebjerg, A., Kragballe, K. & Iversen, L. Tumor necrosis factor α-mediated induction of interleukin 17C in human keratinocytes is controlled by nuclear factor kB. J. Biol. Chem. 286, 25487–25494 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wu, Q. et al. IL-23-dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory Mycoplasma pneumoniae infection. Microbes Infect. 9, 78–86 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Hurst, S.D. et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 169, 443–453 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Li, H. et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc. Natl. Acad. Sci. USA 97, 773–778 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamaguchi, Y. et al. IL-17B and IL-17C are associated with TNF-α production and contribute to the exacerbation of inflammatory arthritis. J. Immunol. 179, 7128–7136 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Spriggs, M.K. Interleukin-17 and its receptor. J. Clin. Immunol. 17, 366–369 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Li, T.S., Li, X.N., Chang, Z.J., Fu, X.Y. & Liu, L. Identification and functional characterization of a novel interleukin 17 receptor: a possible mitogenic activation through ras/mitogen-activated protein kinase signaling pathway. Cell. Signal. 18, 1287–1298 (2006).

    Article  PubMed  Google Scholar 

  41. Chiricozzi, A. et al. Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J. Invest. Dermatol. 131, 677–687 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Kao, C.Y. et al. IL-17 markedly up-regulates β-defensin-2 expression in human airway epithelium via JAK and NF-kB signaling pathways. J. Immunol. 173, 3482–3491 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Abreu, M.T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat. Rev. Immunol. 10, 131–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Apostolaki, M., Armaka, M., Victoratos, P. & Kollias, G. Cellular mechanisms of TNF function in models of inflammation and autoimmunity. Curr. Dir. Autoimmun. 11, 1–26 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Van Maele, L. et al. TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3negCD127+ immune cells in spleen and mucosa. J. Immunol. 185, 1177–1185 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ma, H.L. et al. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J. Clin. Invest. 118, 597–607 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Reiter, M.J., Testerman, T.L., Miller, R.L., Weeks, C.E. & Tomai, M.A. Cytokine induction in mice by the immunomodulator imiquimod. J. Leukoc. Biol. 55, 234–240 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Chiang, E.Y. et al. Targeted depletion of lymphotoxin-α-expressing TH1 and TH17 cells inhibits autoimmune disease. Nat. Med. 15, 766–773 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Neupane and A. Paler-Martinez for cell sorting; A. Abbas for microarray assistance; and J. Ngo and R. Asuncion for mouse colony maintenance.

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Authors and Affiliations

  1. Department of Immunology, Genentech, South San Francisco, California, USA

    Vladimir Ramirez-Carrozzi, Arivazhagan Sambandam, Zhongua Lin, Surinder Jeet, Justin Lesch, Janice Kim, Meijuan Zhou, Wyne Lee, Min Xu, Jason de Voss, Mercedesz Balazs, Harinder Singh, Wenjun Ouyang & Rajita Pappu

  2. Department of Protein Chemistry, Genentech, South San Francisco, California, USA

    Elizabeth Luis & Lino Gonzalez Jr

  3. Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California, USA

    Jason Hackney

  4. Department of Antibody Engineering, Genentech, South San Francisco, California, USA

    Joyce Lai & Tao Sai

  5. Department of Molecular Biology, Genentech, South San Francisco, California, USA

    Zora Modrusan

  6. Department of Pathology, Genentech, South San Francisco, California, USA

    Patrick Caplazi & Lauri Diehl

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  1. Vladimir Ramirez-Carrozzi
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Contributions

V.R.-C. did most of the experiments and analyzed the data; A.S. contributed to identifying the receptors and sources of IL-17C; E.L. and L.G. did the radioligand-binding experiments; Z.L. and M.B. contributed to the imiquimod-induced skin inflammation studies; S.J., J.Lesch, L.D. and J.d.V. did the DSS studies; J.H. analyzed the microarray data; J.K. and M.X. contributed to the adenoviral studies; M.Z. and W.L. did the intradermal IL-17C injections; J.Lai and T.S. generated the mouse antibody to mouse IL-17C; Z.M. contributed to the microarray studies; P.C. contributed to the histological evaluation of the adenoviral, intradermal injection and imiquimod studies; H.S. and W.O. provided scientific input for the project; and R.P. devised and planned the project and wrote the manuscript

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Correspondence to Rajita Pappu.

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All authors are employees of Genentech.

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Ramirez-Carrozzi, V., Sambandam, A., Luis, E. et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol 12, 1159–1166 (2011). https://doi.org/10.1038/ni.2156

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