14^th Euro-Global Gastroenterology Conference

Biography

Biography: Assoc Prof Dr.Prema Robinson

Abstract

Background and Aims: Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory bowel diseases (IBD) of unclear etiology that cause substantial morbidity and predispose to colorectal-cancer (CRC). There are two isoforms of STAT3—a and b; STAT3a is pro-inflammatory and anti-apoptotic, while STAT3b has opposing-effects on STAT3a. We determined the contribution systemically of STAT3 to UC and CD pathogenesis by comparing disease severity caused by dextran sodium sulfate (DSS; UC model) or 2, 4, 6-trinitrobenzenesulfonic acid (TNBS; CD model) in mice expressing only STAT3a (D^b/D^b) and in wild-type (WT) mice treated with TTI-101, a small-molecule inhibitor of both isoforms of STAT3.                                                                                                               

Methods: Seven days following administration of DSS in drinking water or two days following a single intra-rectal administration of TNBS, D^b/D^b mice, cage-control (+/+) mice, and WT mice given TTI-101 or vehicle were examined for IBD manifestations; their colons were evaluated for apoptosis of CD4⁺ T cells, levels of STAT3 activation, IL-17A protein expression, and transcriptome alternations.  

Results: IBD manifestations were increased in D^b/D^b transgenic vs. cage-control WT mice and were accompanied by decreased apoptosis of colonic CD4⁺ T cells. Complementing and extending these results, TTI-101 treatment of WT mice prevented IBD, markedly increased apoptosis of colonic CD4⁺ T cells, reduced colon levels of IL17A-producing cells, and down-modulated STAT3-gene targets involved in inflammation, apoptosis-resistance, and colorectal-cancer metastases.

Conclusions: STAT3, especially in CD4⁺ T cells, contributes to the pathogenesis of UC and CD and its targeting may provide a novel approach to disease treatment.