Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine

Nature volume 491, pages 259–263 (2012)Cite this article

Subjects

Abstract

Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer1. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients2,3. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, also known as IL22RA2); however, the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown4,5. Here we describe that IL-22BP has a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent downregulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumour development if uncontrolled during the recovery phase. Thus, the IL-22–IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Increased tumorigenesis in Il22bp −/− mice in a colitis-associated colon cancer model.
Figure 2: Inverse expression of Il22bp and Il22 during chemical and mechanical intestinal tissue damage.
Figure 3: IL-22BP controls tumorigenesis in APC min/+ mice.
Figure 4: IL-18 regulates Il22bp expression by CD11c + cells.

References

  1. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010)

    Article  CAS  Google Scholar 

  2. Brand, S. et al. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G827–G838 (2006)

    Article  ADS  CAS  Google Scholar 

  3. Wolk, K. et al. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn’s disease. J. Immunol. 178, 5973–5981 (2007)

    Article  CAS  Google Scholar 

  4. Witte, E., Witte, K., Warszawska, K., Sabat, R. & Wolk, K. Interleukin-22: a cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection. Cytokine Growth Factor Rev. 21, 365–379 (2010)

    Article  CAS  Google Scholar 

  5. Sonnenberg, G. F., Fouser, L. A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nature Immunol. 12, 383–390 (2011)

    Article  CAS  Google Scholar 

  6. Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. & Sallusto, F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nature Immunol. 10, 857–863 (2009)

    Article  CAS  Google Scholar 

  7. Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. & Spits, H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nature Immunol. 10, 864–871 (2009)

    Article  CAS  Google Scholar 

  8. Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009)

    Article  CAS  Google Scholar 

  9. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008)

    Article  CAS  Google Scholar 

  10. Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007)

    Article  CAS  Google Scholar 

  11. Kamanaka, M. et al. Memory/effector (CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J. Exp. Med. 208, 1027–1040 (2011)

    Article  CAS  Google Scholar 

  12. Wei, C. C., Ho, T. W., Liang, W. G., Chen, G. Y. & Chang, M. S. Cloning and characterization of mouse IL-22 binding protein. Genes Immun. 4, 204–211 (2003)

    Article  CAS  Google Scholar 

  13. Kotenko, S. V. et al. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immunol. 166, 7096–7103 (2001)

    Article  CAS  Google Scholar 

  14. Xu, W. et al. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc. Natl Acad. Sci. USA 98, 9511–9516 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Dumoutier, L., Lejeune, D., Colau, D. & Renauld, J. C. Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J. Immunol. 166, 7090–7095 (2001)

    Article  CAS  Google Scholar 

  16. Jones, B. C., Logsdon, N. J. & Walter, M. R. Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure 16, 1333–1344 (2008)

    Article  CAS  Google Scholar 

  17. Tanaka, T. et al. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci. 94, 965–973 (2003)

    Article  CAS  Google Scholar 

  18. Becker, C. et al. TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21, 491–501 (2004)

    Article  CAS  Google Scholar 

  19. 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 

  20. Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992)

    Article  ADS  CAS  Google Scholar 

  21. Kinnebrew, M. A. et al. Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276–287 (2012)

    Article  CAS  Google Scholar 

  22. Poritz, L. S. et al. Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. J. Surg. Res. 140, 12–19 (2007)

    Article  CAS  Google Scholar 

  23. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010)

    Article  CAS  Google Scholar 

  24. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011)

    Article  CAS  Google Scholar 

  25. Sivakumar, P. V. et al. Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage. Gut 50, 812–820 (2002)

    Article  CAS  Google Scholar 

  26. Siegmund, B. Interleukin-18 in intestinal inflammation: friend and foe? Immunity 32, 300–302 (2010)

    Article  CAS  Google Scholar 

  27. Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med. 207, 1625–1636 (2010)

    Article  CAS  Google Scholar 

  28. Li, Y. et al. Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCmin/+ mice. Carcinogenesis 33, 1231–1238 (2012)

    Article  CAS  Google Scholar 

  29. Uronis, J. M. e. t. a. l. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS one 4, e6026 (2009)

    Article  ADS  Google Scholar 

  30. Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Med. 15, 1016–1022 (2009)

    Article  CAS  Google Scholar 

  31. Valenzuela, D. M. et al. High-throughput engineering of the mouse genome coupled with high-resolution expression analysis. Nature Biotechnol. 21, 652–659 (2003)

    Article  CAS  Google Scholar 

  32. Sutterwala, F. S. et al. Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327 (2006)

    Article  CAS  Google Scholar 

  33. Okayasu, I., Ohkusa, T., Kajiura, K., Kanno, J. & Sakamoto, S. Promotion of colorectal neoplasia in experimental murine ulcerative colitis. Gut 39, 87–92 (1996)

    Article  CAS  Google Scholar 

  34. Becker, C., Fantini, M. C. & Neurath, M. F. High resolution colonoscopy in live mice. Nature Protocols 1, 2900–2904 (2006)

    Article  CAS  Google Scholar 

  35. O’Connor, W., Jr et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nature Immunol. 10, 603–609 (2009)

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank F. Manzo for expert administrative assistance, E. Eynon and J. Alderman for managing the mouse program. We also thank T. Taylor and G. Tokmoulina for expert help with the FACS sorting. R.A.F. is an Investigator of the Howard Hughes Medical Institute. S.H. was supported by a post-doctoral fellowship from the Crohn’s and Colitis Foundation of America, the ‘Stiftung experimentelle Biomedizin’ and the Ernst Jung Foundation. N.G. was supported by an EMBO post-doctoral fellowship. L.A.Z. was supported by a post-doctoral fellowship from the American Cancer Society. A.J.M., D.M.V. and G.D.Y. were employees of Regeneron Pharmaceuticals at the time this work was performed. W.O. is an employee of Genentech Inc. This work was supported by R01DK077905, DK-P30-34989 and U19-AI082713 (to C.A. and R.A.F.) and by the DFG, SFB841 (to S.H.).

Author information

Author notes

  1. Samuel Huber and Nicola Gagliani: These authors contributed equally to this work.

  2. shuber@uke.de

Authors and Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Samuel Huber, Nicola Gagliani, Lauren A. Zenewicz, Lidia Bosurgi, Bo Hu, William O’Connor & Richard A. Flavell

  2. I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany,

    Samuel Huber & Francis J. Huber

  3. Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, 06520, Connecticut, USA

    Matija Hedl & Clara Abraham

  4. Departments of Medicine and Genetics, Section of Digestive Diseases, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Wei Zhang & Judy H. Cho

  5. Regeneron Pharmaceuticals, Inc., Tarrytown, 10591, New York, USA

    Andrew J. Murphy, David M. Valenzuela & George D. Yancopoulos

  6. Section of Comparative Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Carmen J. Booth

  7. Department of immunology, Genentech, Inc., South San Francisco, California 94080, USA,

    Wenjun Ouyang

  8. Howard Hughes Medical Institute, New Haven, 06520, Connecticut, USA

    Richard A. Flavell

Authors
  1. Samuel Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicola Gagliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lauren A. Zenewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francis J. Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lidia Bosurgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bo Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matija Hedl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William O’Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andrew J. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David M. Valenzuela
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. George D. Yancopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Carmen J. Booth
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Judy H. Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Wenjun Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Clara Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Richard A. Flavell
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.A.F., S.H. and N.G. designed the experiments, analysed the data and wrote the manuscript. L.A.Z. performed colitis-associated colon cancer experiments with Il22−/− single-KO mice, and provided Il22−/− mice. F.J.H. assisted during the mouse endoscopy. L.B. performed immuno histochemistry. B.H. provided mice for colitis-associated cancer experiment. W.O.C. made key suggestions for experiments and edited the manuscript. A.J.M., D.M.V. and G.D.Y. generated Il22bp−/− mice and are employees of Regeneron Pharmaceuticals Inc. C.J.B. performed the histopathological analyses. W.O. provided IL-22 antibody and is an employee of Genentech. W.Z., J.H.C, C.A. and M.H. did the experiments using human material. S.H. and N.G. performed all other experiments.

Corresponding author

Correspondence to Samuel Huber.

Ethics declarations

Competing interests

A.J.M, D.M.V. and G.D.Y. are employees of Regeneron Pharmaceuticals. W.O. is an employee of Genentech Inc.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-12. (PDF 14441 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Huber, S., Gagliani, N., Zenewicz, L. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012). https://doi.org/10.1038/nature11535

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11535

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing