Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic intestinal disorder that is caused by multi-factorial conditions in genetically predisposed individuals. Recently accumulating data from human genome-wide association studies and mouse IBD models have highlighted interleukin-22 (IL-22) pathway as a promising candidate for IBD therapy. The overall objective of this project is to provide a novel intervention to safely enhance the beneficial effect of IL-22 for treatment of IBD particularly UC. In order to achieve the goal, we need to direct an attention to a fact that functions of IL-22 are determined not only by its expression level but also by other factors such as IL-17 and IL-22- binding protein (IL-22BP) that serves as an endogenous inhibitor of IL-22. Indeed, we demonstrated previously that overexpression of IL-22BP impaired the recovery from acute colitis induced by dextran sodium sulfate (DSS). However, only little information is currently available on the IL-22BP in any research fields, including IBD. Our preliminary study found that IL-22BP was highly expressed in normal colon, and this expression level was reduced in the context of inflammation particularly Th1-mediated inflammation. Unexpectedly, we have found that large proportion of immature NK cells exist in the normal colon and they can produce IL-22BP. In contrast, inflammation led to the further maturation of NK cells when IL-22BP expression became undetectable. We demonstrated previously that IL-22 stimulates epithelial cells to produce a mucin 1 (Muc1), a major component in intestinal mucus. Interestingly, we have recently found that the Muc1 contributes to the suppression of Th17 response that has been shown to elicit inflammatory, rather than protective, function of IL-22. Based on these data, we hypothesize that beneficial function of IL- 22 in Th2-mediated chronic colitis is controlled negatively by IL-22BP that suppresses the Muc1-mediated inhibition of Th17 responses, and the colonic expression levels of IL-22BP are determined primarily by the maturation status of conventional NK cells. In this regard, this project will test if absence o IL-22BP improves Th2-mediated chronic colitis (Aim 1.1), whether IL-22BP-anatagonist has therapeutic potential in this colitis (Aim 1.1), if the therapeutic effect can be stable in differet cytokine environments (Aim 1.2), how IL-22BP is constitutively expressed in normal colon (Aim 2.1), how IL-22BP expression is reduced under intestinal inflammatory condition (Aim 2.2), and how the reduction levels are further modified (Aim 2.2).

Public Health Relevance

Recently accumulating data from genetic studies on patients with inflammatory bowel disease clearly highlight a pathway (termed IL-22 pathway) as a promising target for treating this disease more safely and more effectively. Therefore, this project is designed to develop a novel therapeutic strategy to fully maximize the beneficial effect of this pathway in the diseased colon. We believe that our study if fully completed would provide significant contributions for improving the lives of patients with inflammatory bowel disease particularly ulcerative colitis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Hamilton, Frank A
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Massachusetts General Hospital
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Kim, Young-In; Song, Joo-Hye; Ko, Hyun-Jeong et al. (2018) CX3CR1+ Macrophages and CD8+ T Cells Control Intestinal IgA Production. J Immunol 201:1287-1294
Mizoguchi, Atsushi; Yano, Arisa; Himuro, Hidetomo et al. (2018) Clinical importance of IL-22 cascade in IBD. J Gastroenterol 53:465-474
Mohanan, Vishnu; Nakata, Toru; Desch, A Nicole et al. (2018) C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions. Science 359:1161-1166
Maldonado-Contreras, Ana; Birtley, James R; Boll, Erik et al. (2017) Shigella depends on SepA to destabilize the intestinal epithelial integrity via cofilin activation. Gut Microbes 8:544-560
Bouziat, Romain; Hinterleitner, Reinhard; Brown, Judy J et al. (2017) Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356:44-50
Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo et al. (2016) Genetically engineered mouse models for studying inflammatory bowel disease. J Pathol 238:205-19
Subramaniam, Renuka; Mizoguchi, Atsushi; Mizoguchi, Emiko (2016) Mechanistic roles of epithelial and immune cell signaling during the development of colitis-associated cancer. Cancer Res Front 2:1-21
DeGruttola, Arianna K; Low, Daren; Mizoguchi, Atsushi et al. (2016) Current Understanding of Dysbiosis in Disease in Human and Animal Models. Inflamm Bowel Dis 22:1137-50
Li, Yang; Basavappa, Megha; Lu, Jinfeng et al. (2016) Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells. Nat Microbiol 2:16250
Low, Daren; DeGruttola, Arianna K; Poltrak, Alexander et al. (2015) High Endogenous Expression of Chitinase 3-Like 1 and Excessive Epithelial Proliferation with Colonic Tumor Formation in MOLF/EiJ Mice. PLoS One 10:e0139149

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