Prema Robinson
Associate Professor
Title: Genetic and small-molecule modulation of STAT3 in mouse models of infl ammatory bowel disease
Biography
Biography: Prema Robinson
Abstract
Genetic and small-molecule modulation of STAT3 in mouse models of inflammatory bowel disease
Prema Robinson, Ashiq Legi, Amal Khalil, Nikita Engineer, Kelsey Montoya, Emily Magness, Asif Rashid, Kris T Eckols, Cristina Ivan, Peng Yang, Uddalak Bharadwaj and David J Tweardy
The University of Texas MD Anderson Cancer Center, USA
Abstract
Background & 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 β; STAT3a is pro-inflammatory and anti-apoptotic, while STAT3β has opposing-effects on STAT3a. We determined the contribution 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 (Dβ/Dβ) 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, Dβ/Dβ 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 Dβ/Dβ 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.
Conclusion: 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.