Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259-263

1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany [3].
Nature (Impact Factor: 41.46). 10/2012; 491(7423). DOI: 10.1038/nature11535
Source: PubMed


Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer (CRC)1. 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. IL-22, a cytokine of the IL-10 superfamily, plays an important role for colonic epithelial cell repair, and is increased in the blood and intestine of IBD patients2, 3. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, IL-22RA2), however the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown4, 5. We describe herein that IL-22BP plays a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells (DC) in the colon in steady state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent down regulation 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 tumor development if uncontrolled during the recovery phase.
Thus the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

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    • "C-X-C chemokine receptor type 7 is involved in the tumorogenesis process and could become an important target for new anti-metastatic and anti-cancer drugs [49]. Interleukin 22 receptor-alpha 1 is a member of the class II cytokine receptor family, the members of which are often postulated as potential biomarkers for cancerogenesis and tumor progression [50]. Example MS/MS spectra for proteins not present in the analyzed database are in File S2. "
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    • "While in the short term IL-22-mediated survival and proliferation of epithelial cells may favor tissue healing and repair, prolonged IL-22 signaling, and sustained epithelial proliferation may drive tumor formation (79). Accordingly, recent evidence has linked colonic ILC3s to colon cancer in a genetically prone bacterial-driven model of colon cancer (80). "
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    • "Th17 cells secrete characteristic cytokines such as IL-17A, IL-17F, and IL-22 (Grivennikov et al., 2010; Zhu and Qian, 2012). All three Th17 cytokines are required for intestinal tumorigenesis in the Apc min/+ mouse model (Chae and Bothwell, 2011; Chae et al., 2010; Huber et al., 2012). IL-17A also promotes tumor development in other cancer models (Song and Qian, 2013b). "
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