Background & Aim: Colon epithelial cell (CEC) apoptosis and NFkB activation may compromise barrier function, and we have reported that STAT5b deficient mice exhibit increased susceptibility to colitis. We hypothesized that the growth hormone (GH) target, STAT5b maintains mucosal barrier integrity by promoting CEC survival and inhibiting NFkB activation.
Methods: The GH effect upon mucosal injury due to TNBS administration was determined in STAT5b deficient mice and wild type (WT) controls. The effect of STAT5b deficiency upon CEC survival and NFkB activation was determined and related to differences in intestinal permeability and bacterial translocation. RNA interference (RNAi) was used to knock down STAT5b expression in the T84 CEC line and the effect upon basal and GH dependent regulation of pro-apoptotic and inflammatory pathways induced by TNFalpha was determined.
Results: GH suppression of mucosal inflammation in TNBS colitis was abrogated in STAT5b deficient mice. STAT5b deficiency led to activation of a pro-apoptotic pattern of gene expression in the colon, and increased mucosal permeability. The frequency of apoptotic CEC was increased in STAT5b deficient mice while tight junction protein abundance was reduced. This was associated with up regulation of CEC TLR2 expression and NFkappaB activation. STAT5b knock down in T84 CEC increased TNFalpha dependent NFkappaB and caspase 3 activation. Growth hormone (GH) inhibition of TNFalpha signaling was prevented by STAT5b knock down.
Conclusion: STAT5b maintains colonic barrier integrity by modulating CEC survival and NFkappaB activation. STAT5b activation may therefore represent a novel therapeutic target in Inflammatory Bowel Disease.
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