| Objective: Ulcerative colitis(UC) is a chronic inflammatory bowel disease(IBD), whose etiology remains unclear. In clinical practice, although patients could get relief though prescriptions modulating immune response, most patients suffer from an intermittent disease course with periods of remission and relapses. Preliminary studies showed that SOCS3-positive intestinal epithelial cells were significantly increased in colonic mucosa of both inactive and active UC compared with healthy controls, and further analysis revealed that increased SOCS3 expression in intestinal epithelial cells from patients with ulcerative colitis in complete remission(clinical, endoscopic, and histological remission) correlated with shorter time until relapse. This indicated SOCS3 IEC expression during remission may be useful in predicting mucosal relapse in patients without any signs of mucosal inflammation, and high SOCS3 expression in intestinal epithelial cells may play a causative role in UC relapse. C haracterization of the molecular mechanisms involved in contribution of high SOCS3 expression to increased risk for relapse would not only improve our undstanding in the pathogenesis of ulcerative colitis, but also help to devise rational therapeutic strategies in remission maintenance. Recent studies proposed a pivotal role of IL-22/STAT3 signaling pathway in the maintenance of normal epithelial barrier homeostasis, SOCS3 is a classic downstream target of STAT3 and could negatively regulate STAT3 activity. Hence, we hypothesized that IL-22/STAT3 signaling pathway functioned during remission phase of ulcerative colitis, and high SOCS3 expression contributed to relapse of intestinal inflammation through violation of the protective effects of IL-22.Methods: Colonic biopsies from patients with ulcerative colitis in complete remission and healthy controls were obtained and expression of IL-22 as well as downstream targets of IL-22/STAT3 —c-Myc, Survivin were analyzed by immunohistochemistry(IHC). Eukaryotic expression vector of SOCS3 was constructed and SOCS3 stable overexpression epithelial cell line(HC T116, HT29) was obtained. Effects of enforced SOCS3 expression on IL-22-induced proliferation of epithelial was tested by CCK-8assay. Impact of SOCS3 overexpression on epithelial cells wound healing was analyzed employing Wounding assay. Real-time PC R or Westernblot was used to examine the influence of high SOCS3 expression and STAT3 interference on expression of antimicrobial peptides and proliferation-, apoptosis- related protens(Bcl-2, c-Myc, Survivin, Bcl- x L). Periodic acid-Schiff stain(PAS) or real-time PC R was also used to test the impact of SOCS3 on epithelial mucin formation. Finally, influence of SOCS3 on IL-6, IL-13 and IL-22 mediated signal transduction was examined by westernblot.Results:Patients with UC in complete remission showed significantly more mucosal IL-22-positive immune cells as compared with healthy controls, but no difference of epithelial c-Myc and Survivin levels. O verexpression of SOCS3 impaired IL-22-induced epithelial proliferation. Enforced expression of SOCS3 violated IL-22-promoted epithelial wound healing. High SOCS3 expression reduced or nearly abolished IL-22-induced activation of STAT3 and inhibited IL-22/STAT3 mediated expression of antimicrobial peptides, as well as proliferation-, apoptosis- related protens(Bcl-2, c-Myc, Survivin). SOCS3 overexpression also showed violation of epithelial mucus production, and inhibition of IL-6, IL-13, IL-22 induced activation of STAT1, STAT6 and AKT.Conclusion: IL-22/STAT3 signaling pathway may play an important role in mucosal protection in ulcerative colitis in remission. High SOCS3 IEC expression contributed early relapse of ulcerative colitis may due to the violation of IL-22/STAT3- mediated protective effects. Prevention of SOCS3 expression or enhancement of IL-22/STAT3 signaling in IEC seems to be rational therapeutic strategies for UC remission maintenance. |
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