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 3

Rapid attenuation of colitis by local IL-22 gene delivery.

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Rapid attenuation of colitis by local IL-22 gene delivery. (A and B) Com...
(A and B) Complexes of IL-22 secretion or mock vector with DOTAP/enhancer reagent were microinjected into the proximal part of colon of TCRαKO mice with colitis. Expressions of IL-22 in the noninjected distal part and injected proximal part are shown in A. Results represent the averages ± SEM (n = 6–7). **P < 0.005. Protein lysates from the CECs of the proximal part of colon with mock or IL-22 gene delivery were subjected to immunoblot for evaluation of STAT3 activation (B). (C–H) Laparotomy was carried out on anesthetized TCRαKO mice (24 weeks of age) to confirm the presence of severe colitis as indicated by a marked enlargement of colonic diameter (before injection). Local gene delivery of IL-22 or mock vector into the proximal part (just below the ileocecal junction) was performed in selected TCRαKO mice (n = 7 each group) that had severe colitis. Mice were sacrificed 2 weeks after microinjection. IL-22 gene delivery attenuated the inflammation at the injection sites; colonic diameter at the injection sites was markedly reduced in TCRαKO mice that received IL-22 (C, right panels) but not mock (C, left panels) vector delivery. Results are summarized in D. Colonic thickness (E) and disease score (F), which were evaluated by histological examination (n = 6–7), are shown. Histology of the proximal colon where gene delivery with mock (left panel) or IL-22 vector (right panel) was received are shown in G. Original magnification, ×10. (H) Percentages of goblet cells among total epithelial cells within the colon where mock (n = 6) or IL-22 (n = 6) vector delivery were received are shown. *P < 0.001.