Kojima Keishi, Musch Mark W, Ropeleski Mark J, Boone David L, Ma Averil, Chang Eugene B
Martin Boyer Laboratories, Inflammatory Bowel Disease, Research Center, The University of Chicago, Chicago, Illinois 60637, USA.
Am J Physiol Gastrointest Liver Physiol. 2004 Apr;286(4):G645-52. doi: 10.1152/ajpgi.00080.2003. Epub 2003 Nov 20.
Protection of colonic epithelial integrity and function is critical, because compromises in mucosal functions can lead to adverse and potentially life-threatening effects. The gut flora may contribute to this protection, in part, through the sustained induction of cytoprotective heat shock proteins (HSPs) in surface colonocytes. In this study, we investigated whether Escherichia coli LPS mediates bacteria-induced HSP by using cultured young adult mouse colon (YAMC) cells, an in vitro model of the colonic epithelium. E. coli LPS led to an epithelial cell-type specific induction of HSP25 in a time- and concentration-dependent manner, an effect that did not involve changes in HSP72. YAMC cells expressed the toll-like receptors (TLR)2 and TLR4 but not the costimulatory CD14 molecule. Whereas LPS stimulated both the p38 and ERK1/2 but not the stress-activated protein kinase/c-Jun NH(2)-terminal kinase, signaling pathways in the YAMC cells, all three were stimulated in RAW macrophage cells (in which no LPS-induced HSP25 expression was observed). The p38 inhibitor SB-203580 and the MAP kinase kinase-1 inhibitor PD-98059 inhibited HSP25 induction by LPS. LPS treatment also conferred protection against actin depolymerization induced by the oxidant monochloramine. The HSP25 dependence of the LPS protective effect was outlined in inhibitor studies and through adenovirus-mediated overexpression of HSP25. In conclusion, LPS may be an important mediator of enteric bacteria-induced expression of intestinal epithelial HSP25, an effect that may contribute to filamentous actin stabilization under physiological as well as pathophysiological conditions and thus protection of colonic epithelial integrity.
保护结肠上皮的完整性和功能至关重要，因为黏膜功能受损可能导致不良的甚至可能危及生命的后果。肠道菌群可能部分通过在结肠表面细胞持续诱导细胞保护性热休克蛋白（HSPs）来促成这种保护作用。在本研究中，我们使用培养的成年幼鼠结肠（YAMC）细胞（一种结肠上皮的体外模型）来研究大肠杆菌脂多糖（LPS）是否介导细菌诱导的HSP。大肠杆菌LPS以时间和浓度依赖性方式导致上皮细胞类型特异性诱导HSP25，这种效应不涉及HSP72的变化。YAMC细胞表达Toll样受体（TLR）2和TLR4，但不表达共刺激分子CD14。虽然LPS刺激了YAMC细胞中的p38和ERK1/2信号通路，但未刺激应激激活蛋白激酶/c-Jun NH(2)-末端激酶信号通路，而在RAW巨噬细胞（未观察到LPS诱导的HSP25表达）中所有这三条信号通路均被刺激。p38抑制剂SB-203580和丝裂原活化蛋白激酶激酶-1抑制剂PD-98059抑制了LPS诱导的HSP25表达。LPS处理还赋予了对氧化剂一氯胺诱导的肌动蛋白解聚的保护作用。抑制剂研究以及通过腺病毒介导的HSP25过表达概述了LPS保护作用对HSP25的依赖性。总之，LPS可能是肠道细菌诱导肠上皮HSP25表达的重要介质，这种效应可能在生理以及病理生理条件下有助于丝状肌动蛋白的稳定，从而保护结肠上皮完整性。
