IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis
Ken Sugimoto, Atsuhiro Ogawa, Emiko Mizoguchi, Yasuyo Shimomura, Akira Andoh, Atul K. Bhan, Richard S. Blumberg, Ramnik J. Xavier, Atsushi Mizoguchi
Ken Sugimoto, Atsuhiro Ogawa, Emiko Mizoguchi, Yasuyo Shimomura, Akira Andoh, Atul K. Bhan, Richard S. Blumberg, Ramnik J. Xavier, Atsushi Mizoguchi
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Research Article Genetics

IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis

Abstract

Expression of IL-22 is induced in several human inflammatory conditions, including inflammatory bowel disease (IBD). Expression of the IL-22 receptor is restricted to innate immune cells; however, the role of IL-22 in colitis has not yet been defined. We developed what we believe to be a novel microinjection-based local gene-delivery system that is capable of targeting the inflamed intestine. Using this approach, we demonstrated a therapeutic potency for IL-22–mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC). IL-22 gene delivery enhanced STAT3 activation specifically within colonic epithelial cells and induced both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. Importantly, IL-22 gene delivery led to rapid amelioration of local intestinal inflammation. The amelioration of disease by IL-22 was mediated by enhanced mucus production. In addition, local gene delivery was used to inhibit IL-22 activity through overexpression of IL-22–binding protein. Treatment with IL-22–binding protein suppressed goblet cell restitution during the recovery phase of a dextran sulfate sodium–induced model of acute colitis. These data demonstrate what we believe to be a novel function for IL-22 in the intestine and suggest the potency of a local IL-22 gene–delivery system for treating UC.

Authors

Ken Sugimoto, Atsuhiro Ogawa, Emiko Mizoguchi, Yasuyo Shimomura, Akira Andoh, Atul K. Bhan, Richard S. Blumberg, Ramnik J. Xavier, Atsushi Mizoguchi

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Figure 1

Enhancement of STAT3 activation in CECs by IL-22.

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Enhancement of STAT3 activation in CECs by IL-22. (A) Expression levels ...
(A) Expression levels of IL-22 in normal colon of WT (n = 9) and inflamed colon of TCRαKO (TCRα) mice (n = 9) and the CD45RB colitis model (n = 4). (B) Expression levels of IL-22 in intestinal biopsy samples from healthy controls (n = 10) and from patients with UC (n = 12) or CD (n = 9) are shown. (C) Expression levels of IL-22 in purified CD4+ T cells and IgM+ cells from inflamed colon of TCRαKO mice are shown. (D) Expression levels of IL-22 in purified CD4+ T cells from inflamed colon of TCRαKO mice and CD45RB model are shown. (E) Expressions of β-actin, IL-22RA1, and IL-10R2 in CECs (red lines) and colonic LP (black lines) of TCRαKO mice. Results represent averages of 4 different experiments ± SEM. Quantitative data relative to β-actin expression are summarized in the 2 right panels. (F and G) Freshly isolated CECs from WT mice were stimulated with various doses of IL-22 for 15 minutes (F). Normal human colonic tissues were stimulated without (cont) or with 10 ng/ml of IL-22 (G). Protein lysates (10 μg) were immunoblotted with anti–phospho-STAT3 (P-STAT3) or anti–phospho–ERK1/2 Abs. After stripping the Abs, the membrane was reprobed with anti-STAT3 or anti-ERK1/2 Abs. The result is representative of 3 individual experiments. (H) Human colonic specimen was stimulated without (top panel) or with IL-22 (bottom panel) for 2 hours and subjected to immunohistochemical analysis using anti–phospho-STAT3 Abs. Original magnification, ×40.