title: Differential Requirements for IL-17A and IL-22 in Cecal versus Colonic Inflammation Induced by Helicobacter hepaticus.
abstract: Type 17 helper T-cell cytokines have been implicated in the pathogenesis of inflammatory bowel disease, a chronic condition affecting the gastrointestinal tract, but information regarding their contribution to pathology in different regions of the gut is lacking. By using a murine model of bacteria-induced typhlocolitis, we investigated the role of IL-17A, IL-17F, and IL-22 in cecal versus colonic inflammation. Cecal, but not colonic, pathology in C57BL/6 mice inoculated with Helicobacter hepaticus plus anti-IL-10 receptor (IL-10R) monoclonal antibody was exacerbated by co-administration of anti-IL-17A monoclonal antibody, suggesting a disease-protective role for IL-17A in the cecum. In contrast, anti-IL-17F had no effect on H. hepaticus-induced intestinal pathology. Neutralization of IL-22 prevented the development of colonic, but not cecal, inflammation in H. hepaticus-infected anti-IL-10R-treated mice, demonstrating a pathogenic role for IL-22 in the colon. Analysis of transcript levels revealed differential expression of IL-22R, IL-22 binding protein, and IL-23R between cecum and colon, a finding that may help explain why these tissues respond differently after anti-IL-22 treatment. Analysis of microarray data from healthy human intestine further revealed significant differences in cytokine receptor transcript levels (including IL-22RA1 and IL-23R) in distinct parts of the human gut. Together, our findings demonstrate that individual type 17 helper T-cell cytokines can have proinflammatory or anti-inflammatory effects in different regions of the intestine, an observation that may have implications for interventions against human inflammatory bowel disease.
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Morrison
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Ballantyne
authors.affiliation: Centre for Chronic Diseases and Disorders, Department of Biology, University of York, York, United Kingdom.
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Macdonald
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: John W J
authors.initials: JW
authors.lastname: Moore
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Jenkins
authors.affiliation: Development Operations, Pfizer Biotherapeutics Research and Development, Cambridge, Massachusetts.
authors.forename: Jill F
authors.initials: JF
authors.lastname: Wright
authors.affiliation: Development Operations, Pfizer Biotherapeutics Research and Development, Cambridge, Massachusetts.
authors.forename: Lynette A
authors.initials: LA
authors.lastname: Fouser
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom. Electronic address: marika.kullberg@york.ac.uk.
authors.forename: Marika C
authors.initials: MC
authors.lastname: Kullberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D003092:Colitis / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control; D005260:Female; D015870:Gene Expression / Q000276:immunology; D016481:Helicobacter Infections / Q000276:immunology*; D044923:Helicobacter hepaticus; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007422:Intestines / Q000276:immunology; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D018121:Receptors, Cytokine / Q000096:biosynthesis; D053706:Typhlitis / Q000276:immunology / Q000382:microbiology*; D000097043:Interleukin-22
chemical_list: D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D007378:Interleukins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D000097043:Interleukin-22