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 7

Effect of IL-22BP on the suppression of IL-22 activity in vivo.

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Enhanced mucus production mediates IL-22–induced rapid attenuation of UC...
(A) Expression levels of IL-22BP (ratio of IL-22BP/β-actin) in the colonic LP at days 0 (normal), 4 (acute phase), and 8 (recovery phase) of DSS colitis are shown. (B–F) Local IL-22BP gene delivery was performed in the proximal part of the colon, and the mice were subsequently treated with 3% DSS on the third day after the delivery. DSS treatment was terminated at day 5 after initiation, and mice were sacrificed at day 8. Expression of IL-22BP in the distal (noninjected site) and proximal (injected site) colons of mice with mock or IL-22BP gene delivery is shown (B). CECs were freshly isolated from DSS-treated WT mice that had received local gene delivery of mock or IL-22BP vector in the proximal colon. Protein lysates from the freshly isolated CECs were subjected to immunoblot with anti–phospho-STAT3 Abs (C). After stripping the Abs, the membrane was reprobed with anti-STAT3 Abs (C). The proximal colon of mock (left panel) or IL-22BP (right panel) gene–delivered mice was subjected to Alcian blue staining (D). Significant reduction of goblet cells (blue) is observed in the colon of IL-22BP–delivered mice as compared with that of mock-delivered mice. Ulceration is indicated by arrow. Original magnification, ×4. Averages of goblet cells/field in the noninjected (distal colon) and injected (proximal colon) site are shown in E. Disease score in the proximal colon (injected site) is summarized in F. *P< 0.05; **P< 0.005; ***P< 0.001.