Neutralizing antibodies against IgG, IL-17A, or IFN- were administered to 3-week old Th1 polarization was increased while Th17 polarization was impaired in KSR1 deficient na?ve T cells. neutralizing antibodies attenuated colitis in and 0.05, ** 0.01, *** 0.001 Expression of KSR1 in hematopoietic lineages is protective against colitis The disease that develops in and 2panels 1 & 4). Interestingly, restoring IL-10 to the immune system in and 2panel 3). However, restoring KSR1 to the immune system in and 2panel 2). Interestingly, reconstitution of irradiated GSK9311 WT mice with (Supplemental Figures 2& 2 0.05, ** 0.01 Lamina propria T cells isolated from KSR1?/? and KSR1?/?Il10?/? mice have increased IFN- production Pro-inflammatory cytokines including TNF, IFN-, and IL-17 are increased in the intestinal mucosa of Crohns disease patients and in mouse models of IBD.18C22 Therefore, we determined relative transcript levels of Th1 and Th17 cytokines in the colonic mucosa of WT, 0.05, ** 0.01, *** 0.001 Open in a separate window Figure 4 Lamina propria T cells isolated from 0.05, ** 0. 01 In vitro Th1 polarization is enhanced while Th17 polarization is impaired in KSR1 deficient T cells IL-17A production by Th17 effector cells has been implicated in the pathogenesis of diseases including rheumatoid arthritis, multiple sclerosis, and Crohns disease.23C25 Our previous observations that IL-17A transcripts and protein levels were altered in mice lacking KSR1 suggested that KSR1 may be involved in T cell development along the Th1/Th17 axis. To test this, we isolated splenocytes from WT, Th17 polarization is impaired while Th1 polarization is increased in 0.05, ** 0.01, *** 0.001 Neutralization of IFN- attenuates severity of disease in KSR1?/?Il10?/? mice Our data showing that colons of & 6 0.05, ** 0.01 Discussion While distinct roles for KSR1 have been reported for intestinal epithelial cells,12, 13 T cell proliferation,26 T cell differentiation,27, 28 and recently NK cell-mediated cytolysis,29 the role of KSR1 in inflammatory diseases has not been defined. In this study, we utilized the IL-10 deficiency-induced mouse model of spontaneous experimental colitis to investigate the role of KSR1 during chronic inflammation. We found that while Th17 development was impaired. Finally, administration of IFN- neutralizing antibody attenuated colitis severity in Th1 polarization was elevated in KSR1 deficient T Mouse monoclonal to PRMT6 cells suggests a potential pathway by which KSR1 deficiency might exacerbate colitis in & 5locus were linked to IBD and GSK9311 other autoimmune disorders.46 Vitamin D supplementation holds promise as a therapeutic agent in the treatment of Crohns disease by increasing NOD2 expression that then couples to the expression the antimicrobial peptide defensin 2.47 Interestingly, the promoter region contains a vitamin D responsive element and GSK9311 moreover, KSR1 protein is upregulated by 1, 25-dihydroxyvitamin D3.28 In fact, em VDR /em ?/? em Il10 /em ?/? mice GSK9311 develop severe accelerated spontaneous colitis harboring many phenotypic similarities to those observed in em KSR1 /em ?/? em Il10 /em ?/? mice including increased levels of IFN-.48, 49 It is attractive to speculate that vitamin D-mediated suppression of pathogenic immune responses is, in part, regulated by KSR1 expression and suppression of IFN- production in Th1 effector cells. We conclude that KSR1 expression suppresses IFN- production in T lymphocytes and promotes T cell developmental homeostasis along the Th1/Th17 axis. Therefore, induction of KSR1 expression may be an ideal strategy for modulating IFN- in Th1-mediated diseases. Supplementary Material 01Click here to view.(173K, pdf) 02Click here to view.(1.1M, pdf) 03Click here to view.(314K, pdf) 04Click here to view.(906K, pdf) 05Click here to view.(349K, pdf) 06Click here to view.(2.7M, pdf) Acknowledgements We thank Valerie Hilliard for helpful critique of this manuscript, Amy Major for assistance with bone GSK9311 marrow transplantation, Abudi.