Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
Int Immunopharmacol. 2018 Feb;55:336-344. doi: 10.1016/j.intimp.2017.12.016. Epub 2018 Jan 8.
Recent studies have linked impairment of intestinal epithelial function in inflammatory bowel disease to the disturbance of endoplasmic reticulum homeostasis (ER) in response to stress. Most studies are on goblet and Paneth cells, which are considered more susceptible to stress due to their role in the protection of intestinal epithelium against microbes and harmful substances. However, studies on the role of inflammation-induced ER stress in absorptive intestinal cells are scarce. In this study, we show, using Caco-2 cells as a model of intestinal epithelial barrier, that inducing ER stress using a cocktail mixture of pro-inflammatory mediators [TNFα (50ng/ml), MCP1 (50ng/ml), and IL-1β (25ng/ml)] as observed in IBD patients induces ER stress and leads to significant changes in key proteins of the apical (sucrase-isomaltase (SI), dipeptidyl-peptidase (DPPIV), and ezrin) and basolateral (E-cadherin, zonula occludens (ZO-1), and connexin-43) membranes. Aberrant trafficking of SI, DPPIV was observed as early as 8h post-inflammation-induced ER stress and even in the absence of loss of intestinal cell integrity. The observed effect was associated with a re-localization of ezrin, ZO-1, and connexin-43, key differentiation and junction proteins. Collectively, this study shows that disruption of the trafficking of key digestive enzymes of the intestinal epithelium occur in response to inflammation induced ER stress before the loss of monolayer integrity.
最近的研究将炎症性肠病中肠上皮功能的损伤与内质网稳态（ER）的紊乱联系起来，以应对应激。大多数研究集中在杯状细胞和潘氏细胞上，由于它们在保护肠上皮免受微生物和有害物质侵害方面的作用，这些细胞被认为更容易受到应激的影响。然而，关于炎症诱导的 ER 应激在吸收性肠细胞中的作用的研究还很少。在这项研究中，我们使用 Caco-2 细胞作为肠上皮屏障的模型，表明在 IBD 患者中观察到的促炎介质（TNFα（50ng/ml）、MCP1（50ng/ml）和 IL-1β（25ng/ml））混合物诱导 ER 应激，导致关键蛋白在上皮细胞（蔗糖酶-异麦芽糖酶（SI）、二肽基肽酶（DPPIV）和 ezrin）和基底外侧（E-钙粘蛋白、紧密连接蛋白（ZO-1）和连接蛋白-43）膜的显著变化。在炎症诱导的 ER 应激后 8 小时，甚至在肠细胞完整性没有丧失的情况下，就观察到 SI 和 DPPIV 的异常转运。观察到的效应与 ezrin、ZO-1 和连接蛋白-43 的重定位有关，这些是关键的分化和连接蛋白。总之，这项研究表明，在单层完整性丧失之前，肠上皮细胞的关键消化酶的运输就会因炎症诱导的 ER 应激而中断。
