Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
Mol Immunol. 2012 Oct;52(3-4):264-72. doi: 10.1016/j.molimm.2012.06.007. Epub 2012 Jun 27.
Intestinal epithelial cells (IECs) form a physical barrier between the internal milieu and the intestinal microflora via the expression of tight junctions. TLR-mediated recognition of intestinal microflora by IECs is important for tight junction preservation, production of chemokines, and cell survival. Disturbance of the IEC barrier function results in bacterial invasion and contributes to the development of inflammatory bowel disease. We observed that muramyl dipeptide (MDP), a breakdown product of bacterial peptidoglycan, strongly enhances subsequent Toll-like receptor (TLR) responses in murine colonic epithelium cell lines. Prior exposure to MDP significantly increased the production of chemokines and cytokines and improved the barrier function induced by different TLR2 and TLR4 ligands. shRNA knock-down studies showed that MDP recognition by Nod2 mediated the enhancement of TLR responses. Our studies indicate that Nod2 stimulation by MDP significantly enhances TLR-mediated IEC barrier function and chemokine production. Failure of this protective mechanism may contribute to the increased risk of Crohn's disease in individuals with a loss-of-function mutation in NOD2.
肠上皮细胞 (IECs) 通过表达紧密连接在内部环境和肠道微生物群之间形成物理屏障。IEC 对肠道微生物群的 TLR 介导的识别对于保持紧密连接、趋化因子的产生和细胞存活很重要。IEC 屏障功能的紊乱导致细菌入侵，并有助于炎症性肠病的发展。我们观察到，细菌肽聚糖的降解产物 muramyl dipeptide (MDP) 强烈增强了鼠结肠上皮细胞系中随后的 Toll 样受体 (TLR) 反应。预先暴露于 MDP 可显著增加趋化因子和细胞因子的产生，并改善不同 TLR2 和 TLR4 配体诱导的屏障功能。shRNA 敲低研究表明，Nod2 通过识别 MDP 介导 TLR 反应的增强。我们的研究表明，MDP 对 Nod2 的刺激可显著增强 TLR 介导的 IEC 屏障功能和趋化因子的产生。这种保护机制的失败可能导致 NOD2 功能丧失突变个体中克罗恩病风险增加。
