Regulation of intestinal barrier function by signal transducer and activator of transcription 5b

Abstract

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.

KRAB Zinc Finger Protein ZNF382 Is a Proapoptotic Tumor Suppressor That Represses Multiple Oncogenes and Is Commonly Silenced in Multiple Carcinomas

“…Some targets are NF-κB upstream regulatory factors, such as STAT3, STAT5B, ID1, and IKBKE. STAT3 and STAT5B are required for maintaining NF-κB activity (27,28). ID1 promotes cell survival by regulating NF-κB activity in prostate and breast cancers (30,43); IKBKE is an oncogene controlling the activity of NF-κB in cell proliferation and malignant transformation (29).…”

“…6A). Some of these oncogenes were known to be NF-κB pathway upstream effectors, such as STAT3, STAT5B, IKBKE, and ID1 (27)(28)(29)(30). Thus, ZNF382 could inhibit the NF-κB pathway by suppressing its upstream effectors.…”

PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice

“…Induction of IEC apoptosis has also been described in a number of studies using murine colitis models (6)(7)(8). IEC apoptosis can disrupt intestinal mucosal integrity and barrier function and lead to other changes associated with colitis (9,10). Furthermore, anti-TNF therapies for treating IBD patients were found to inhibit IEC apoptosis (11,12).…”

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

“…H&E-stained paraffin sections were imaged and used for pathological evaluation. Sections were scored by a pathologist and a histological score of colitis was assessed as: 0, no inflammation; 1, very low levels of inflammation, low level of leukocytic infiltration; 2, low level of leukocytic infiltration; 3) high level of leukocytic infiltration, high vascular density, thickening of the colon wall; 4) transmural infiltrations, loss of goblet cells, high vascular density, thickening of the colon wall (22,23).…”