Differential requirements for IL-17A and IL-22 in cecal versus colonic inflammation induced by Helicobacter hepaticus

Th17-type cytokines have been implicated in the pathogenesis of inflammatory bowel disease (IBD), but no information is available regarding the contribution of these cytokines to pathology in different regions of the gut. To address this issue, we have used the Helicobacter hepaticus typhlocolitis model to investigate the role of IL-17A, IL-17F, and IL-22 in cecal versus colonic inflammation. We report that cecal, but not colonic pathology in C57BL/6 mice inoculated with H. hepaticus plus anti-IL-10R mAb is exacerbated by co-administration of anti-IL-17A mAb, suggesting a disease-protective role for IL-17A in the cecum. In contrast, anti-IL-17F had no effect on H. hepaticus-induced large 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. By assessing transcript levels, we provide evidence that differential expression of IL-22R, IL-22BP and IL-23R between cecum and colon may help explain why these tissues respond differently following anti-IL-22 treatment. Analysis of microarray data from healthy human intestine further revealed significant differences in cytokine receptor transcript levels (including IL22RA1 and IL23R) in distinct parts of the human gut. Together, our findings demonstrate that individual Th17-type cytokines can have pro- or anti-inflammatory effects in different regions of the intestine, an observation that may have implications for interventions against human IBD.