Robinson Prema, Magness Emily, Montoya Kelsey, Engineer Nikita, Eckols Thomas K, Rodriguez Emma, Tweardy David J
Departments of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-3772, USA.
Molecular & Cellular Oncology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-3772, USA.
J Clin Med. 2022 Nov 28;11(23):7020. doi: 10.3390/jcm11237020.
Crohn's disease (CD), is an inflammatory bowel disease that can affect any part of the gastro-intestinal tract (GI) and is associated with an increased risk of gastro-intestinal cancer. In the current study, we determined the role of genetic and small-molecule modulation of STAT3 in a mouse model of CD. STAT3 has 2 isoforms (α, β) which are expressed in most cells in a 4:1 ratio (α: β). STAT3α has pro-inflammatory and anti-apoptotic functions, while STAT3β has contrasting roles. We used an animal model of CD consisting of intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid and examined the severity of CD in transgenic-mice that express only STAT3α (∆/∆), as well as in wild-type (WT) mice administered TTI-101 (formerly C188-9), a small molecule STAT3 inhibitor. We determined that clinical manifestations of CD, such as mortality, rectal-bleeding, colonic bleeding, diarrhea, and colon shortening, were exacerbated in ∆/∆ transgenic versus cage-control WT mice, while they were markedly decreased by TTI-101 treatment of WT mice. TTI-101 treatment also increased apoptosis of pathogenic CD4 T cells and reduced colon levels of IL-17-positive cells. Our results indicate that STAT3 contributes to CD and that targeting of STAT3 with TTI-101 may be a useful approach to treating CD.
克罗恩病（CD）是一种炎症性肠病，可影响胃肠道（GI）的任何部位，并与胃肠道癌症风险增加相关。在本研究中，我们确定了STAT3的基因和小分子调节在CD小鼠模型中的作用。STAT3有2种异构体（α、β），它们在大多数细胞中以4:1的比例（α:β）表达。STAT3α具有促炎和抗凋亡功能，而STAT3β则具有相反的作用。我们使用了一种CD动物模型，通过直肠内给予2,4,6-三硝基苯磺酸，并检测了仅表达STAT3α的转基因小鼠（∆/∆）以及给予小分子STAT3抑制剂TTI-101（原C188-9）的野生型（WT）小鼠中CD的严重程度。我们确定，与笼养对照WT小鼠相比，∆/∆转基因小鼠中CD的临床表现，如死亡率、直肠出血、结肠出血、腹泻和结肠缩短等情况加剧，而WT小鼠经TTI-101治疗后这些表现明显减轻。TTI-101治疗还增加了致病性CD4 T细胞的凋亡，并降低了结肠中IL-17阳性细胞的水平。我们的结果表明，STAT3促成了CD的发生，用TTI-101靶向STAT3可能是治疗CD的一种有效方法。
