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 antieIL-10 receptor (IL-10R) monoclonal antibody was exacerbated by co-administration of antieIL-17A monoclonal antibody, suggesting a disease-protective role for IL-17A in the cecum. In contrast, antieIL-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 antieIL-10Retreated 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 antieIL-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. (Am J Pathol 2015, 185: 3290e3303; http://dx

Helicobacter hepaticuscytolethal distending toxin promotes intestinal carcinogenesis in 129Rag2-deficient mice

“…whereas, anti-Il-17 treatment increased severity of cecal pathology but not colonic pathology (Kullberg et al, 2006;Morrison et al, 2015). Thus, it is possible that the progression of preneoplastic dysplasia to cancer promoted by HhCDT requires a host factor(s) and a defined microflora only present in the ceca and ileocecocoloic junction.…”

“…Consistent with these previous findings, in the Hh‐infected mice, there was more severe pathology in the ceca and ileocecocolic junction compared with transverse and distal colon at both time points and in the HhCDT mutant‐infected mice at 10 WPI. In addition, previous studies in anti‐Il10R‐treated C57BL/6 mice reported that Il‐22 and Ifnγ are required for inducing colonic inflammation but not for cecal inflammation by H. hepaticus ; whereas, anti‐Il‐17 treatment increased severity of cecal pathology but not colonic pathology (Kullberg et al, ; Morrison et al, ). Thus, it is possible that the progression of preneoplastic dysplasia to cancer promoted by HhCDT requires a host factor(s) and a defined microflora only present in the ceca and ileocecocoloic junction.…”

NovelHelicobacterspeciesH.japonicumisolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10−/−mice

“…In our study, there were no differences in the cecum typhlocolitis index scores between genders, but the female mice had significantly higher pathological scores in the colon at both 6 and 10 weeks p.i. The underlying differences in the expression of cytokine receptors in different anatomical locations of the intestine may contribute to this difference (39). At 6 weeks p.i, multifocal hepatitis was noticed in the infected mice which may indicate H.japonicum infection in the liver by translocating the intestinal barrier into hepatic tissues or alternatively, indirect effect of systemic cytokine response due to the primary intestinal infection (40).…”

Other Helicobacters and gastric microbiota

“…H. hepaticus‐ or H. typhlonius ‐infected mice are frequently used as a model for a better understanding of the pathogenesis of inflammatory bowel diseases in humans. IL‐23 produced by monocytes, IL‐17 and IL‐22 produced by Th17 cells, IFNγ and IL‐17 produced by Th1/17 cells, and TNFα produced by colitogenic T cells seem to be associated with the development of intestinal inflammation. Ray et al .…”