Immunity, Infection and Inflammation Program, Mater Medical Research Institute and the University of Queensland, Mater Health Services, South Brisbane, QLD 4101, Australia.
Biochem Soc Trans. 2011 Aug;39(4):1081-5. doi: 10.1042/BST0391081.
Data from animal models and human inflammatory bowel diseases have implicated the ER (endoplasmic reticulum) stress pathway in intestinal inflammation. We have characterized the development of inflammation in Winnie mice in which ER stress arises due to a single missense mutation in the MUC2 mucin produced by intestinal goblet cells. This model has allowed us to explore the genesis of inflammation ensuing from a single gene polymorphism affecting secretory cells. In these mice, a proportion of MUC2 misfolds during biosynthesis, leading to ER stress and activation of the unfolded protein response. Winnie mice develop spontaneous complex progressive inflammation that is most severe in the distal colon. Inflammation involves TH1, TH2 and TH17 T-cells, with a progressive development of a TH17-dominated response, but also involves innate immunity, in a pattern not dissimilar to human colitis. Experimental inhibition of tolerance in this model severely exacerbates colitis, demonstrating active effective suppression of inflammation. Even though the misfolding of MUC2 is a consequence of an inherited mutation, as inflammation develops, the molecular markers of ER stress increase further and goblet cell pathology becomes worse, suggesting that inflammation itself exacerbates ER stress.
来自动物模型和人类炎症性肠病的数据表明内质网（ER）应激途径与肠道炎症有关。我们已经描述了由于肠杯状细胞产生的 MUC2 粘蛋白的单个错义突变而导致 ER 应激的 Winnie 小鼠中炎症的发展。该模型使我们能够探索由影响分泌细胞的单个基因多态性引起的炎症的发生。在这些小鼠中，一部分 MUC2 在生物合成过程中错误折叠，导致 ER 应激和未折叠蛋白反应的激活。Winnie 小鼠自发发展复杂的进行性炎症，在远端结肠最为严重。炎症涉及 TH1、TH2 和 TH17 T 细胞，随着 TH17 主导反应的逐渐发展，但也涉及固有免疫，与人类结肠炎的模式相似。在该模型中实验性抑制耐受会严重加剧结肠炎，表明炎症得到了积极有效的抑制。尽管 MUC2 的错误折叠是遗传突变的结果，但随着炎症的发展，ER 应激的分子标志物进一步增加，杯状细胞病变变得更糟，表明炎症本身加剧了 ER 应激。
