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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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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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