KSR1 protects from interleukin-10 deficiency-induced colitis in mice by suppressing T-lymphocyte interferon-? production.

ABSTRACT: Immunological 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.KSR1(-/-)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-? (IFN-?) production analyzed by flow cytometry. Neutralizing antibodies against IgG, IL-17A, or IFN-? were administered to 3-week-old KSR1(-/-)Il10(-/-) mice for 3 weeks and scored for colitis.KSR1(-/-)Il10(-/-) mice developed accelerated and severe spontaneous colitis by 4 weeks of age. KSR1 expression in hematopoietic lineages was protective against colitis. Both IFN-? and IL-17A transcripts were elevated in colons of KSR1(-/-) and KSR1(-/-)Il10(-/-) mice. IFN-? 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-? neutralizing antibodies attenuated colitis in KSR1(-/-)Il10(-/-) mice.Mice lacking both KSR1 and IL-10 develop exacerbated colitis due to dysregulated IFN-? production in T lymphocytes.

SUBMITTER: Goettel JA 

PROVIDER: S-EPMC3008308 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature