Xu Lu, Xu Fangyue, Yao Qinghua, Wong Vincent Kam Wai
Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.
Front Pharmacol. 2025 Aug 29;16:1572534. doi: 10.3389/fphar.2025.1572534. eCollection 2025.
This study aimed to evaluate the therapeutic effects of Ruxolitinib, a JAK1/2 inhibitor, on DSS-induced acute colitis in mice, with a focus on its impact on disease activity, inflammatory responses, modulation of myeloid-derived suppressor cells (MDSCs), and regulation of the JAK/STAT1 signaling pathway.
Acute UC was induced in C57BL/6 mice by administering a 2.5% DSS solution. Mice were randomly assigned to three groups: the blank group (no DSS), the model group (DSS only), and the Ruxolitinib-treated group (DSS +30 mg/kg Ruxolitinib by gavage for 14 consecutive days). Body weight, disease activity index (DAI) scores, spleen weight, and colon length were measured. Spleen index and the spleen weight-to-colon length ratio were calculated. Flow cytometry was used to assess the proportion of MDSCs in the blood. , CCD841 and Jurkat cells were pretreated with 50 IU/mL IFN-γ for 2 h, followed by 24-h treatment with Ruxolitinib. PCR array analysis was performed to identify transcriptional changes in JAK-STAT pathway-related genes. Electrophoretic mobility shift assay (EMSA) and Western blot were used to investigate the inhibition of STAT1 activation and phosphorylation.
, DSS-induced acute colitis in the model group, and Ruxolitinib treatment significantly alleviated colitis as evidenced by reduced body weight loss (p < 0.05), decreased DAI scores in the later stages (p < 0.05), a lower spleen index (p < 0.05), increased colon length (p < 0.01), and a reduced spleen weight-to-colon length ratio (p < 0.05). Flow cytometry revealed a significant reduction in the proportion of CD11b Gr-1 MDSCs in the blood of the Ruxolitinib group compared to the model group (p < 0.01). , PCR array analysis showed that Ruxolitinib notably downregulated the transcription of several JAK-STAT pathway-related genes, including B2M, IRF1, RQ1, SOCS1, STAT1, and STAT3, with STAT1 showing the most pronounced changes. EMSA and Western blot analysis confirmed that Ruxolitinib effectively inhibited IFN-γ-induced STAT1 activation and phosphorylation in a dose-dependent manner.
Ruxolitinib effectively ameliorated DSS-induced acute colitis by reducing inflammation, modulating MDSC levels, and inhibiting STAT1 activation. These findings suggest that Ruxolitinib could be a promising therapeutic agent for UC, targeting both the immune response and the JAK/STAT1 signaling pathway.
本研究旨在评估JAK1/2抑制剂鲁索替尼对葡聚糖硫酸钠（DSS）诱导的小鼠急性结肠炎的治疗效果，重点关注其对疾病活动度、炎症反应、髓源性抑制细胞（MDSC）的调节作用以及JAK/STAT1信号通路的调控。
通过给予2.5% DSS溶液诱导C57BL/6小鼠发生急性溃疡性结肠炎（UC）。将小鼠随机分为三组：空白组（未给予DSS）、模型组（仅给予DSS）和鲁索替尼治疗组（DSS + 30 mg/kg鲁索替尼灌胃，连续14天）。测量体重、疾病活动指数（DAI）评分、脾脏重量和结肠长度。计算脾脏指数和脾脏重量与结肠长度之比。采用流式细胞术评估血液中MDSC的比例。将CCD841和Jurkat细胞用50 IU/mL IFN-γ预处理2小时，随后用鲁索替尼处理24小时。进行PCR阵列分析以鉴定JAK-STAT通路相关基因的转录变化。采用电泳迁移率变动分析（EMSA）和蛋白质免疫印迹法（Western blot）研究STAT1激活和磷酸化的抑制情况。
模型组出现DSS诱导的急性结肠炎，鲁索替尼治疗显著减轻了结肠炎，表现为体重减轻减少（p < 0.05）、后期DAI评分降低（p < 0.05）、脾脏指数降低（p < 0.05）、结肠长度增加（p < 0.01）以及脾脏重量与结肠长度之比降低（p < 0.05）。流式细胞术显示，与模型组相比，鲁索替尼组血液中CD11bGr-1 MDSC的比例显著降低（p < 0.01）。PCR阵列分析表明，鲁索替尼显著下调了几个JAK-STAT通路相关基因的转录，包括B2M、IRF1、RQ1、SOCS1、STAT1和STAT3，其中STAT1的变化最为明显。EMSA和Western blot分析证实，鲁索替尼以剂量依赖性方式有效抑制IFN-γ诱导的STAT1激活和磷酸化。
鲁索替尼通过减轻炎症、调节MDSC水平和抑制STAT1激活，有效改善了DSS诱导的急性结肠炎。这些发现表明，鲁索替尼可能是一种有前景的UC治疗药物，可同时针对免疫反应和JAK/STAT1信号通路。
