Immunity, Infection and Inflammation Program, Mater Medical Research Institute and The University of Queensland, Mater Health Services, South Brisbane, Queensland, Australia.
Gut. 2011 Dec;60(12):1661-70. doi: 10.1136/gut.2011.239194. Epub 2011 Jun 2.
The MUC13 transmembrane mucin is highly and constitutively expressed in the small and large intestine. Although MUC13 polymorphisms have been associated with human inflammatory bowel diseases and susceptibility to Escherichia coli infection in pigs, the biological functions of MUC13 are unknown. This study aimed to explore whether MUC13 modulates intestinal inflammation.
Muc13(-/-) mice were generated, phenotyped and challenged with the colitis-inducing agent, dextran sodium sulphate (DSS). Colitis was assessed by clinical symptoms and intestinal histopathology. Intestinal epithelial cell apoptosis and proliferation, macrophage infiltration and cytokine production were also quantified. Apoptosis of human LS513 intestinal epithelial cells in response to apoptotic agents, including DSS, was also measured, following knockdown of MUC13 with siRNA.
Muc13(-/-) mice were viable, fertile and developed normally, with no spontaneous intestinal pathology except mild focal neutrophilic inflammation in the small and large intestines of old mice. In response to DSS challenge, Muc13(-/-) mice developed more severe acute colitis, as reflected by increased weight loss, rectal bleeding, diarrhoea and histological colitis scores compared with wild-type mice. Increased numbers of F4/80(+) macrophages in inflamed mucosa of Muc13(-/-) mice were accompanied by increased expression of intestinal IL-1β and TNFα mRNA. Muc13(-/-) mice had significantly increased intestinal epithelial cell apoptosis within 3 days of DSS exposure. LS513 cells were more susceptible to DSS, actinomycin-D, ultraviolet irradiation and TRAIL-induced apoptosis when MUC13 was knocked down by siRNA.
These novel findings indicate a protective role for Muc13 in the colonic epithelium by inhibiting toxin-induced apoptosis and have important implications for intestinal infections, inflammatory diseases and the development of intestinal cancer.
MUC13 跨膜粘蛋白在小肠和大肠中高度且持续表达。尽管 MUC13 多态性与人类炎症性肠病和猪对大肠杆菌感染的易感性有关，但 MUC13 的生物学功能尚不清楚。本研究旨在探讨 MUC13 是否调节肠道炎症。
生成 Muc13(-/-) 小鼠，表型分析并接受结肠炎诱导剂葡聚糖硫酸钠（DSS）的挑战。通过临床症状和肠道组织病理学评估结肠炎。还定量了肠道上皮细胞凋亡和增殖、巨噬细胞浸润和细胞因子产生。还通过 siRNA 敲低 MUC13 测量了人 LS513 肠道上皮细胞对凋亡剂（包括 DSS）的反应性凋亡。
Muc13(-/-) 小鼠具有活力、繁殖力和正常发育，除了老年小鼠的小肠和大肠中有轻微的局灶性中性粒细胞炎症外，没有自发的肠道病理学。在 DSS 挑战下，与野生型小鼠相比，Muc13(-/-) 小鼠发展出更严重的急性结肠炎，表现为体重减轻、直肠出血、腹泻和组织学结肠炎评分增加。在 Muc13(-/-) 小鼠的炎症黏膜中，F4/80(+) 巨噬细胞的数量增加，伴随着肠道 IL-1β 和 TNFα mRNA 的表达增加。Muc13(-/-) 小鼠在 DSS 暴露后的 3 天内，肠道上皮细胞凋亡明显增加。当用 siRNA 敲低 MUC13 时，LS513 细胞对 DSS、放线菌素 D、紫外线照射和 TRAIL 诱导的凋亡更敏感。
这些新发现表明 Muc13 通过抑制毒素诱导的凋亡在结肠上皮中发挥保护作用，这对肠道感染、炎症性疾病和肠道癌症的发展具有重要意义。
