Editors' ChoiceImmunology

Preventing Tumorigenesis, Promoting Tissue Repair

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Science Signaling  13 Nov 2012:
Vol. 5, Issue 250, pp. ec290
DOI: 10.1126/scisignal.2003773

Interleukin-22 (IL-22), a cytokine implicated in innate immunity that binds receptors only on nonimmune cells, promotes tissue repair by inducing epithelial cell proliferation but can also promote pathological inflammatory responses. Uncontrolled cell proliferation and pathological inflammation can both lead to cancer. A soluble form of the IL-22 receptor (IL-22BP) binds IL-22, preventing IL-22 from activating its membrane-associated receptor. Huber et al. investigate the regulation of IL-22BP and the effect of IL-22BP on tumorigenesis in the intestine. They generated IL-22BP–deficient (Il22bp–/–) mice and treated them with dextran sodium sulfate (DSS) to make animal models for acute and chronic colitis and colitis-associated colon cancer. There was no difference in disease severity between wild-type and Il22bp–/– mice in acute and chronic colitis models, but Il22bp–/– mice had increased numbers and sizes of tumors in the colitis-associated colon cancer model. After recovery from DSS-induced colitis, more cells in colon crypts from Il22bp–/– than from wild-type mice incorporated BrdU, indicating greater cell proliferation, and colon tissue from Il22bp–/– mice had more epithelial cells positive for markers of proliferating cells than did tissue from wild-type mice. There were also more tumor cells positive for markers of proliferating cells in tumors from Il22bp–/– compared with those from wild-type mice. There was decreased Il22bp mRNA and increased Il22 mRNA abundance in colon tissues at the peak of DSS-induced colitis compared with the start of the disease or after intestinal damage by mechanical wounding compared with before wounding. Cellular analysis showed that IL22BP was produced by intestinal dendritic cells. The decrease in Il22bp mRNA abundance in response to mechanical wounding depended on components of the NLRP3 or NLRP6 inflammasomes, which are activated by factors produced during tissue damage or microbial ligands, or IL-18, which is proteolytically activated by the inflammasome but did not require signaling by Toll-like receptors (TLRs, which are activated by pathogen-derived ligands).Thus, activation of inflammasomes by tissue damage reduces the production of IL22BP to allow IL-22–mediated repair. These studies indicate that the right balance of IL22BP is necessary to prevent tumorigenesis but enable tissue repair.

S. Huber, N. Gagliani, L. A. Zenewicz, F. J. Huber, L. Bosurgi, B. Hu, M. Hedl, W. Zhang, W. O’Connor Jr., A. J. Murphy, D. M. Valenzuela, G. D. Yancopoulos, C. J. Booth, J. H. Cho, W. Ouyang, C. Abraham, R. A. Flavell, IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012). [PubMed]

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