The JAK-Inhibitor Tofacitinib Rescues Human Intestinal Epithelial Cells and Colonoids from Cytokine-Induced Barrier Dysfunction
The JAK-Inhibitor Tofacitinib Rescues Human Intestinal Epithelial Cells and Colonoids from Cytokine-Induced Barrier Dysfunction
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DOI：
10.1093/ibd/izz266
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发表时间：
2020-03-01
影响因子：
4.9
通讯作者：
McCole, Declan F.
中科院分区：
文献类型：
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作者：
Sayoc-Becerra, Anica;Krishnan, Moorthy;McCole, Declan F.
通过进行一系列粪便微生物群移植实验，我们显示了从缓解期IBD供体分离的人肠道微生物群和IBD小鼠模型中健康对照的人肠道微生物群对回肠炎严重程度的可变影响。炎症性肠病（IBD）的早期关键事件。托法替尼（Xeljanz）是一种口服泛Janus激酶（JAK）抑制剂，最近被批准用于治疗中度至重度溃疡性结肠炎。然而，托法替尼对肠上皮细胞功能的影响在很大程度上是未知的。本研究的目的是确定托法替尼对JAK的抑制是否可以挽救尼古丁诱导的肠上皮细胞（IEC）屏障功能障碍。方法采用T-84 IEC评估托法替尼对JAK信号转导和转录激活因子（STAT）激活、屏障通透性以及紧密连接蛋白表达和定位的影响。在HT-29 IEC中评估托法替尼对密蛋白-2启动子活性的影响。Tofacitinib救援的屏障功能也在人类结肠干细胞衍生的organoids.Results预处理与tofacitinib防止IFN-γ诱导的跨上皮电阻（TER）的降低和4 kDa的FITC-葡聚糖渗透性（FD 4）的增加，部分原因是紧密连接蛋白2的转录调控和ZO-1重排的限制。尽管在IFN-γ激发后给予托法替尼仅使TER和claudin-2水平部分正常化，但FD 4渗透性和ZO-1定位完全恢复。IFN-γ诱导的FD 4渗透性在主要的人类结肠样完全获救tofacitinib.Conclusions这些数据表明，不同的治疗效果的托法替尼在救援孔与密封连接屏障缺陷，并表明改善上皮屏障功能的潜在贡献，托法替尼在IBD患者的有益影响。
By conducting a series of fecal microbiota transplantation experiments, we show a variable effect on ileitis severity from human gut microbiota isolated from IBD donors in remission and that of healthy controls in a mouse model of IBD.AbstractBackground Alterations to epithelial tight junctions can compromise the ability of the epithelium to act as a barrier between luminal contents and the underlying tissues, thereby increasing intestinal permeability, an early critical event in inflammatory bowel disease (IBD). Tofacitinib (Xeljanz), an orally administered pan-Janus kinase (JAK) inhibitor, was recently approved for the treatment of moderate to severe ulcerative colitis. Nevertheless, the effects of tofacitinib on intestinal epithelial cell functions are largely unknown. The aim of this study was to determine if JAK inhibition by tofacitinib can rescue cytokine-induced barrier dysfunction in intestinal epithelial cells (IECs).Methods T-84 IECs were used to evaluate the effects of tofacitinib on JAK-signal transducer and activator of transcription (STAT) activation, barrier permeability, and expression and localization of tight junction proteins. The impact of tofacitinib on claudin-2 promoter activity was assessed in HT-29 IECs. Tofacitinib rescue of barrier function was also tested in human colonic stem cell-derived organoids.Results Pretreatment with tofacitinib prevented IFN-gamma-induced decreases in transepithelial electrical resistance (TER) and increases in 4 kDa FITC-dextran permeability (FD4), partly due to claudin-2 transcriptional regulation and restriction of ZO-1 rearrangement at tight junctions. Although tofacitinib administered after IFN-gamma challenge only partially normalized TER and claudin-2 levels, FD4 permeability and ZO-1 localization were fully recovered. The IFN-gamma-induced FD4 permeability in primary human colonoids was fully rescued by tofacitinib.Conclusions These data suggest differential therapeutic efficacy of tofacitinib in the rescue of pore vs leak-tight junction barrier defects and indicate a potential contribution of improved epithelial barrier function to the beneficial effects of tofacitinib in IBD patients.