Ruxolitinib Alleviates Inflammation, Apoptosis, and Intestinal Barrier Leakage in Ulcerative Colitis via STAT3

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  • 作者:Li Chunxiao, Xu Yu, Gao Tengjiao, Zhang Shunyao, Lin Zhe, Gu Shaobo, Fang Yi, Yuan Xin, Yu Siyi, Jiang Qi, Lou Zhongze, Zhang Xiuming, Zhang Jie, Wu Qiaoyan, Gu Mengli, Ding Xiaoyun, Sun Jing, Chen Yi
  • 期刊:INFLAMMATORY BOWEL DISEASES
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BackgroundUlcerative colitis (UC) is an idiopathic, chronic in?ammatory disorder of the colonic mucosa with increasing prevalence and limited management. Ruxolitinib is a new anti- JAK/STAT3 biologic agent that has shown potential in protecting against colitis.MethodsWe first constructed an in vivo UC model and an in vitro colonic epithelial cell inflammation model. Ruxolitinib was administered via gavage in mice. After treatment, colon tissues, cells, and cell lysates were collected and prepared for histological evaluation, immunohistochemistry, immunofluorescence staining, quantitative reverse-transcriptase polymerase chain reaction, Western blotting, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining, and cytokine analysis. STAT3 expression was silenced and overexpressed via small interfering RNA and overexpression plasmid transfection, respectively, and quantitative reverse-transcriptase polymerase chain reaction was used to examine the downstream effects.ResultsRuxolitinib administration significantly alleviated colitis both in vivo and in vitro, as manifested by reduced body weight loss, shortened colon lengths, relieved disease activity (measured by the disease activity index), and prolonged survival. A mechanistic study showed that ruxolitinib attenuated nuclear factor kappa B–induced inflammation, reduced apoptosis, and ameliorated epithelial barrier leakage, and thereby reduced colitis activity in vivo. STAT3 knockdown partially reversed the protective effect of ruxolitinib against colitis, while STAT3 overexpression exaggerated the reductions in proinflammatory cytokine levels upon ruxolitinib treatment.ConclusionsWe demonstrate that ruxolitinib alleviates colitis by inhibiting nuclear factor kappa B–related inflammation and apoptosis in addition to restoring epithelial barrier function via STAT3, providing a new strategy for UC treatment.

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