title: 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.affiliation: Experimental Pathology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ogawa
authors.forename: Emiko
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Shimomura
authors.forename: Akira
authors.initials: A
authors.lastname: Andoh
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizoguchi
mesh_terms: D000818:Animals; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D020397:Goblet Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009093:Mucus / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22