Differential Requirements for IL-17A and IL-22 in Cecal versus Colonic Inflammation Induced by Helicobacter hepaticus

作者:Morrison Peter J; Ballantyne Sarah J; Macdonald Sandy J; Moore John W J; Jenkins David; Wright Jill F; Fouser Lynette A; Kullberg Marika C*
来源:American Journal Of Pathology, 2015, 185(12): 3290-3303.
DOI:10.1016/j.ajpath.2015.08.015

摘要

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 proinfiammatory or anti-inflammatory effects in different regions of the intestine, an observation that may have implications for interventions against human inflammatory bowel disease.

  • 出版日期2015-12