Department of Gastroenterology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Gastroenterology, Ningbo First Hospital, Ningbo, China.
Inflamm Bowel Dis. 2023 Aug 1;29(8):1191-1201. doi: 10.1093/ibd/izad007.
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory 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.
We 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.
Ruxolitinib 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.
We 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.
溃疡性结肠炎（UC）是一种特发性、慢性结肠黏膜炎症性疾病，其患病率不断增加，且治疗方法有限。鲁索利替尼是一种新型的抗 JAK/STAT3 生物制剂，已显示出在预防结肠炎方面的潜力。
我们首先构建了体内 UC 模型和体外结肠上皮细胞炎症模型。通过灌胃给予鲁索利替尼治疗。治疗后，收集结肠组织、细胞和细胞裂解物，进行组织学评估、免疫组织化学、免疫荧光染色、定量逆转录聚合酶链反应、Western blot、末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记染色和细胞因子分析。通过小干扰 RNA 和过表达质粒转染分别沉默和过表达 STAT3 表达，并进行定量逆转录聚合酶链反应检测下游效应。
鲁索利替尼给药在体内和体外均显著缓解结肠炎，表现为体重减轻减少、结肠缩短减轻、疾病活动度（通过疾病活动指数测量）减轻和生存时间延长。机制研究表明，鲁索利替尼减弱了核因子 κB 诱导的炎症，减少了细胞凋亡，并改善了上皮屏障渗漏，从而减轻了体内结肠炎的活动度。STAT3 敲低部分逆转了鲁索利替尼对结肠炎的保护作用，而 STAT3 过表达加剧了鲁索利替尼治疗后促炎细胞因子水平的降低。
我们证明鲁索利替尼通过抑制核因子 κB 相关炎症和细胞凋亡以及通过 STAT3 恢复上皮屏障功能来缓解结肠炎，为 UC 的治疗提供了一种新策略。
