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 6

Role of IL-22 in the restitution of goblet cells during recovery from acute intestinal injury.

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Effect of IL-22BP on the suppression of IL-22 activity in vivo. (A) Expr...
(A) DSS was administered into WT mice for 5 days and the treatment terminated to induce recovery phase. Expression levels of IL-22 (ratio of IL-22/β-actin) in the colonic LP at days 0 (normal), 4 (acute phase), 8, 12 (recovery phases), and 24 are shown (n = 4 each group). (B) CECs were freshly isolated as crypt units from WT mice and stimulated with IL-22 (5 ng/ml) in the presence or absence of anti–IL-22 Abs. Protein lysates (10 μg) from the stimulated CECs were subjected to immunoblot with anti–phospho-STAT3 (P-STAT3) Abs. After stripping Abs, the membrane was reprobed with anti-STAT3 Abs (STAT3). (C–E) WT mice were treated with 3.5% DSS in drinking water for 5 days. Repeated i.p. administration of 1.5 mg/injection of anti–IL-22 Abs (@IL22; n = 12) or control Ig (Cont; n = 12) was performed at days 4, 5, 6, and 7 in selected mice that showed similar body weight loss at day 4 as compared with initial body weight. Body weight change (C), “Swiss rolls” (D, upper panels), and high magnification (D, bottom panels) of colons stained with Alcian blue are shown. *P < 0.05; **P < 0.005; ***P < 0.001. Original magnification, ×1 (E, top row); ×20 (E, bottom row). Disease scores are summarized in E.