Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Immunity. 2012 Aug 24;37(2):326-38. doi: 10.1016/j.immuni.2012.05.024. Epub 2012 Aug 16.
The intracellular sensor NOD1 has important host-defense functions relating to a variety of pathogens. Here, we showed that this molecule also participates in the induction of a noninfectious pancreatitis via its response to commensal organisms. Pancreatitis induced by high-dose cerulein (a cholecystokinin receptor agonist) administration depends on NOD1 stimulation by gut microflora. To analyze this NOD1 activity, we induced pancreatitis by simultaneous administration of a low dose of cerulein (that does not itself induce pancreatitis) and FK156, an activator of NOD1 that mimics the effect of gut bacteria that have breached the mucosal barrier. The pancreatitis was dependent on acinar cell production of the chemokine MCP-1 and the intrapancreatic influx of CCR2(+) inflammatory cells. Moreover, MCP-1 production involved activation of the transcription factors NF-κB and STAT3, each requiring complementary NOD1 and cerulein signaling. These studies indicate that gut commensals enable noninfectious pancreatic inflammation via NOD1 signaling in pancreatic acinar cells.
胞内传感器 NOD1 具有与多种病原体相关的重要宿主防御功能。在这里，我们表明，该分子还通过其对共生生物的反应参与诱导非传染性胰腺炎。通过高剂量鹅脱氧胆酸（胆囊收缩素受体激动剂）给药诱导的胰腺炎取决于肠道微生物群对 NOD1 的刺激。为了分析这种 NOD1 活性，我们通过同时给予低剂量鹅脱氧胆酸（其本身不引起胰腺炎）和 FK156 来诱导胰腺炎，FK156 是 NOD1 的激活剂，模拟了已突破黏膜屏障的肠道细菌的作用。胰腺炎依赖于趋化因子 MCP-1 的胰腺腺泡细胞产生和 CCR2（+）炎性细胞的胰内流入。此外，MCP-1 的产生涉及转录因子 NF-κB 和 STAT3 的激活，每个都需要互补的 NOD1 和鹅脱氧胆酸信号。这些研究表明，肠道共生菌通过胰腺腺泡细胞中的 NOD1 信号使非传染性胰腺炎得以发生。
