Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.
EMBO Mol Med. 2012 Feb;4(2):109-24. doi: 10.1002/emmm.201100192. Epub 2012 Jan 9.
Epithelial myosin light chain kinase (MLCK)-dependent barrier dysfunction contributes to the pathogenesis of inflammatory bowel diseases (IBD). We reported that epithelial GM-CSF-STAT5 signalling is essential for intestinal homeostatic response to gut injury. However, mechanism, redundancy by STAT5 or cell types involved remained foggy. We here generated intestinal epithelial cell (IEC)-specific STAT5 knockout mice, these mice exhibited a delayed mucosal wound healing and dysfunctional intestinal barrier characterized by elevated levels of NF-κB activation and MLCK, and a reduction of zonula occludens expression in IECs. Deletion of MLCK restored intestinal barrier function in STAT5 knockout mice, and facilitated mucosal wound healing. Consistently, knockdown of stat5 in IEC monolayers led to increased NF-κB DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which were potentiated by administration of tumour necrosis factor-α (TNF-α), and prevented by concurrent NF-κB knockdown. Collectively, enterocyte STAT5 signalling protects against TJ barrier dysfunction and promotes intestinal mucosal wound healing via an interaction with NF-κB to suppress MLCK. Targeting IEC STAT5 signalling may be a novel therapeutic approach for treating intestinal barrier dysfunction in IBD.
上皮细胞肌球蛋白轻链激酶（MLCK）依赖性屏障功能障碍导致炎症性肠病（IBD）的发病机制。我们报道上皮细胞 GM-CSF-STAT5 信号对肠道损伤的肠道稳态反应是必不可少的。然而，机制、STAT5 的冗余或涉及的细胞类型仍然不清楚。我们在这里生成了上皮细胞特异性 STAT5 敲除小鼠，这些小鼠表现出黏膜愈合延迟和肠屏障功能障碍，其特征是 NF-κB 激活和 MLCK 水平升高，以及上皮细胞中紧密连接（TJ）表达减少。在 STAT5 敲除小鼠中，MLCK 的缺失恢复了肠道屏障功能，并促进了黏膜愈合。同样，在 IEC 单层细胞中敲低 stat5 会导致 NF-κB 与 MLCK 启动子的结合增加，肌球蛋白轻链磷酸化和 TJ 通透性增加，这一过程可被肿瘤坏死因子-α（TNF-α）增强，并可通过同时敲低 NF-κB 来预防。总之，肠上皮细胞 STAT5 信号通过与 NF-κB 相互作用抑制 MLCK，从而防止 TJ 屏障功能障碍并促进肠道黏膜愈合。针对 IEC STAT5 信号的治疗方法可能是治疗 IBD 中肠道屏障功能障碍的一种新的治疗方法。
