KSR1 Protects From Interleukin-10 Deficiency-Induced Colitis in Mice by Suppressing T-Lymphocyte Interferon-γ Production

Background & AimsImmunological disorders of the gastrointestinal tract such as inflammatory bowel disease often result in recurrent and persistently elevated levels of proinflammatory cytokines. Kinase suppressor of Ras 1 (KSR1) is involved in tumor necrosis factor−mediated colon epithelial cell survival, yet its role in chronic inflammation has not been defined. In this study, we tested the hypothesis that KSR1 is protective against spontaneous experimental colitis.MethodsKSR1−/−Interleukin-10 (Il10)−/− mice were generated and histolopathologic parameters of intestinal inflammation were scored. Bone marrow transplants performed on wild-type and KSR1−/−Il10−/− mice determined the contribution of KSR1 in hematopoietic lineages. Mucosal T helper (Th) 1 and Th17 cytokine were also examined. In vitro Th1 and Th17 polarization assays were conducted and interleukin (IL)-17A and interferon-γ (IFN-γ) production analyzed by flow cytometry. Neutralizing antibodies against IgG, IL-17A, or IFN-γ were administered to 3-week-old KSR1−/−Il10−/− mice for 3 weeks and scored for colitis.ResultsKSR1−/−Il10−/− mice developed accelerated and severe spontaneous colitis by 4 weeks of age. KSR1 expression in hematopoietic lineages was protective against colitis. Both IFN-γ and IL-17A transcripts were elevated in colons of KSR1−/− and KSR1−/−Il10−/− mice. IFN-γ production was increased in lamina propria T cells isolated from KSR1−/− and KSR1−/−Il10−/− mice. Additionally, in vitro Th1 polarization was increased while Th17 polarization was impaired in KSR1-deficient naïve T cells. Finally, administration of IFN-γ neutralizing antibodies attenuated colitis in KSR1−/−Il10−/− mice.ConclusionsMice lacking both KSR1 and IL-10 develop exacerbated colitis due to dysregulated IFN-γ production in T lymphocytes.