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
View: Text | PDF
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

×

Figure 7

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

Options: View larger image (or click on image) Download as PowerPoint
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.