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 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.