IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis
Ken Sugimoto, … , Ramnik J. Xavier, Atsushi Mizoguchi
Ken Sugimoto, … , Ramnik J. Xavier, Atsushi Mizoguchi
Published January 2, 2008
Citation Information: J Clin Invest. 2008;118(2):534-544. https://doi.org/10.1172/JCI33194.
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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 4

IL-22–mediated induction of a series of Muc expressions in CECs through STAT3 activation.

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IL-22–mediated induction of a series of Muc expressions in CECs through ...
(A and B) CECs were freshly isolated from WT mice that had received local gene delivery of mock (white bars, n = 5) or IL-22 secretion (black bars, n = 5) vector into the proximal colon. Expressions of MUCs by CECs are shown in A. Protein lysates from freshly isolated CECs were subjected to immunoblot with anti–phospho-STAT3 (P-STAT3) or anti-MUC1 (MUC1) Abs (B). After stripping the Abs, the membrane was reprobed with anti-STAT3 (STAT3) or actin Abs. (C and D) Average expressions of MUCs by T84 cells stimulated with IL-22 (10 ng/ml) in duplicates of 3 individual experiments are shown in C. Protein lysates were immunoblotted with anti-MUC1 Abs (D). After stripping the Abs, membrane was reprobed with β-actin Abs. (E) T84 cells were transfected with a combination of STAT3 shRNA vectors (pKD-STAT3-v2 and -v3) or STAT1 shRNA vectors (pKD-STAT1-v1 and -v2) using Amaxa, which has been shown to efficiently transfect the gene of interest into cells resistant to typical transfection approaches. Cell line with mock vector transfection was used as control. After stimulation of the shRNA- or mock vector–transfected cells with IL-22 (10 ng/ml), the efficiency of the combined shRNA on the silencing of STAT3 or STAT1 expression was confirmed by Western blot (upper left panels) and real-time PCR analyses (upper right panels). Expression of MUC1, -3, and -13 by shRNA (STAT3 or STAT1) or mock vector–transfected cells stimulated with IL-22 was evaluated by real-time PCR analysis. Data represent the average of 3 individual experiments. **P < 0.005; *P < 0.05.