IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine
Open Access
- 17 October 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 491 (7423), 259-263
- https://doi.org/10.1038/nature11535
Abstract
IL-22 is one of the factors that, although important for wound healing, also promote tumorigenesis; the regulation of IL-22BP, the IL-22 binding protein, via the NLRP3 and NLRP6 inflammasomes provides an unanticipated mechanism, controlling IL-22 and thereby the development of colon cancer. IL-22-binding protein (IL-22BP) is a soluble receptor that specifically binds to and neutralizes the cytokine interleukin (IL) 22, but its physiological function in vivo is unknown. Using a new IL-22BP-knockout mouse strain, this study shows that IL-22BP is required for epithelial tissue repair in a mouse model of colitis and to prevent the development of colon cancer owing to unrestrained IL-22-mediated epithelial proliferation. IL-22BP is downregulated by an inflammasome- and IL-18-dependent mechanism after initial tissue damage to allow for repair. 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 publication has 35 references indexed in Scilit:
- Interleukin 23 Production by Intestinal CD103+CD11b+ Dendritic Cells in Response to Bacterial Flagellin Enhances Mucosal Innate Immune DefenseImmunity, 2012
- NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for ColitisCell, 2011
- Memory/effector (CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22–dependent intestinal pathologyThe Journal of Experimental Medicine, 2011
- MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18The Journal of Experimental Medicine, 2010
- The InflammasomesCell, 2010
- Immunity, Inflammation, and CancerCell, 2010
- A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responsesNature Medicine, 2009
- A protective function for interleukin 17A in T cell–mediated intestinal inflammationNature Immunology, 2009
- Innate and Adaptive Interleukin-22 Protects Mice from Inflammatory Bowel DiseaseImmunity, 2008
- Structure of IL-22 Bound to Its High-Affinity IL-22R1 ChainStructure, 2008