Heat shock transcription factor 2 predicts mucosal healing and promotes mucosal repair of ulcerative colitis.

Background: Mucosal healing(MH) is a treatment goal in ulcerative colitis (UC). Our previous studies showed heat shock transcription factor 2 (HSF2) was positively correlated with the activity of UC and had anti-inflammatory potential in DSS-induced colitis, but the role of HSF2 in MH remains unknown. This study aimed to reveal the predictive value and mechanisms of HSF2 in the MH of UC.Methods: Fecal samples were collected from 51 UC patients and 10 healthy controls. Correlation analyses among HSF2, fecal calprotectin(FC) and Mayo endoscopic subscore(MES) were conducted by Pearson correlation coefficient. Diagnostic accuracy and cutoffs to predict MH were analyzed by ROC curves. 231 UC patients were enrolled to verify the diagnostic validity of the cutoffs. HSF2 siRNA and HSF2-FLAG recombinant plasmids were transfected into HT-29 cells. IL-1ß, TNF-α and TGF-ß levels in supernatants were determined by ELISA. The expression and phosphorylation levels of MAPKs and Smad2/3 were detected by Western blotting.Results: Positive correlations existed between HSF2 and MES (r = 0.81), FC and MES (r = 0.85), and HSF2 and FC (r = 0.91). Optimal cutoffs of HSF2 was 1.97 ng/ml (AUC 0.919) and that of FC was 678 µg/g (AUC 0.958). HSF2 and FC achieved high sensitivity (73.7% vs 84.2%) and negative predictive value (89.1% vs 93.9%). HSF2 decreased IL-1ß and TNF-α secretion via suppression of MAPK signaling pathway activation. HSF2 promoted the expression of TGF-ß via increasing phosphorylation of Smad2/3.Conclusions: HSF2 may be a predictor of MH in UC patients. HSF2 inhibited inflammation and promoted mucosal repair.

Heat shock transcription factor 2 inhibits intestinal epithelial cell apoptosis through the mitochondrial pathway in ulcerative colitis.

UC is a chronic inflammatory disease of the colonic mucosa and lacks effective treatments because of unclear pathogenesis. Excessive apoptosis of IECs damages the intestinal epithelial barrier and is involved in the progression of UC, but the mechanism is unknown. HSPs are important in maintaining homeostasis and regulate apoptosis through the mitochondrial pathway. In our previous studies, HSF2, an important regulator of HSPs, was highly expressed in UC patients and negatively correlated with inflammation in mice and IECs. Therefore, we hypothesized that HSF2 may protect against intestinal mucositis by regulating the apoptosis of IECs. In this study, a DSS-induced colitis model of hsf2-/- mice was used to explore the relationship between HSF2 and apoptosis in IECs for the first time. The expression of HSF2 increased in the WT + DSS group compared with that in the WT + H2O group. Moreover, the extent of apoptosis was more severe in the KO + DSS group than in the WT + DSS group. The results showed that HSF2 was negatively correlated with apoptosis in vivo. The expression of HSF2 in Caco-2 cells was changed by lentiviral transfection, and the expression of Bax, cytoplasmic Cyto-C, Cleaved Caspase-9 and Cleaved Caspase-3 were negatively correlated with the different levels of HSF2. These results suggest that HSF2 negatively regulates apoptosis of IECs through the mitochondrial pathway. This may be one of the potential mechanisms to explain the protective role of HSF2 in UC.