Background: Colon epithelial cell (CEC) apoptosis and nuclear factor-κB (NF-κB) activation may compromise barrier function, and it has been reported that signal transducer and activator of transcription 5b (STAT5b)-deficient mice exhibit increased susceptibility to colitis. It is hypothesised that the growth hormone (GH) target STAT5b maintains mucosal barrier integrity by promoting CEC survival and inhibiting NF-κB activation.
Methods: The GH effect upon mucosal injury due to 2,4,6-trinitro-benzenesulfonic acid (TNBS) administration was determined in STAT5b-deficient mice and wild-type (WT) controls. The effect of STAT5b deficiency upon CEC survival and NF-κB 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 proapoptotic and inflammatory pathways induced by tumour necrosis factor α (TNFα) was determined.
Results: GH suppression of mucosal inflammation in TNBS colitis was abrogated in STAT5b-deficient mice. STAT5b deficiency led to activation of a proapoptotic pattern of gene expression in the colon, and increased mucosal permeability. The frequency of apoptotic CECs was increased in STAT5b-deficient mice while tight junction protein abundance was reduced. This was associated with upregulation of CEC Toll-like receptor 2 expression and NF-κB activation. STAT5b knockdown in T84 CEC increased TNFα-dependent NF-κB and caspase-3 activation. GH inhibition of TNFα signalling was prevented by STAT5b knockdown.
Conclusion: STAT5b maintains colonic barrier integrity by modulating CEC survival and NF-κB activation. STAT5b activation may therefore represent a novel therapeutic target in inflammatory bowel disease.
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▸ Additional figures are published online only at http://gut.bmj.com/content/vol58/issue1
Funding: Grant support was obtained from the Crohns and Colitis Foundation of America (XH) and NIH grant R01 DK058259 (LAD).
Competing interests: None.