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 5

Enhanced mucus production mediates IL-22–induced rapid attenuation of UC-like disease.

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Role of IL-22 in the restitution of goblet cells during recovery from ac...
(A–D) Laparotomy was carried out on anesthetized TCRαKO mice (24 weeks of age) to confirm the presence of colitis as indicated by a marked enlargement of colonic diameter (A, before injection). Local gene delivery of IL-22 vector into the proximal part (just below the ileocecal junction) was performed in the diseased TCRαKO mice. PBS (A, left panels) or mucolytic agent (A, right panels) was continuously administered into the cecal lumen through osmotic pump for 2 weeks. The mice were sacrificed 2 weeks after the microinjection (A, after injection). Numbers in panels indicate the colonic diameter. Summary of change in colonic diameter of 4 mouse groups (n = 4–6) (IL-22 gene delivery plus PBS treatment, black; IL-22 gene delivery plus mucolytic treatment, red; mock gene delivery plus mucolytic treatment, blue; and mock gene delivery plus PBS treatment, green) is shown in B. Histology of the colon from IL-22–gene–delivered TCRαKO mice with PBS (C, left panels) or mucolytic agent (C, right panels) and summarized disease score (D) are shown. (E) Alcian blue staining shows preserved mucus layer (blue liner, arrowhead) along epithelial surface of IL-22–gene–delivered TCRαKO mice (left panels). In contrast, mucolytic treatment impaired the mucus layer formation with significant adhesion of enteric bacteria (arrow; middle panels). Adhesion of enteric bacteria was confirmed by toluidine blue staining (top right panel, arrow). Average (randomly selected 20 fields/each mouse of 4 mice) of thicknesses of bacterial layer attached to epithelial surface is summarized in bottom right panel. **P < 0.001. Original magnification, ×1 (C); ×10 (E, top left panels); ×40 (E, bottom left panels).