Krueger Sabine, Hundertmark Tanja, Kalinski Thomas, Peitz Ulrich, Wex Thomas, Malfertheiner Peter, Naumann Michael, Roessner Albert
Institute of Pathology, Department of Gastroenterology, Hepatology and Infectious Diseases, Magdeburg, Germany.
J Biol Chem. 2006 Feb 3;281(5):2868-75. doi: 10.1074/jbc.M511053200. Epub 2005 Dec 1.
Helicobacter pylori colonizes the human gastric epithelium and induces an inflammatory response that is a trigger for gastric carcinogenesis. Matrix metalloproteinases (MMPs) have recently been shown to be up-regulated in gastric epithelial cells infected with H. pylori and might contribute to the pathogenesis of peptic ulcer. The aim of this study was to extend the knowledge about the effect of H. pylori infection on MMP-1 expression by gastric epithelial cells, the kinetics of induction, the pathogenetic properties of the bacterium, and the intracellular signaling pathways required for MMP-1 up-regulation. Expression of MMP-1 was induced more than 10-fold by co-culture of AGS+cells with H. pylori strains carrying the pathogenicity island (PAI). H. pylori strains with mutations in the PAI and a defective type IV secretion system had no effect on MMP-1. Double immunofluorescence revealed strong MMP-1 staining in epithelial cells of gastric biopsies at sites of bacterial attachment. In vitro, MMP-1 is up-regulated by interleukin-1beta and tumor necrosis factor-alpha, but these regulatory mechanisms are not operating in H. pylori infection as shown by inhibitory antibodies. Specific inhibitors of JNK kinase and ERK1/2 kinase were found to suppress the H. pylori-induced MMP-1 expression and activity. AGS cells treated with antisense MMP-1 showed a significantly reduced potential to degrade reconstituted basement membrane. Our results suggest that in gastric epithelial cells, H. pylori up-regulates MMP-1 in a type IV secretion system-dependent manner via JNK and ERK1/2. Induction of MMP-1 is further implicated in complex processes induced by H. pylori, resulting in tissue degradation and remodeling of the gastric mucosa.
幽门螺杆菌定殖于人类胃上皮细胞，并引发炎症反应，这是胃癌发生的一个触发因素。基质金属蛋白酶（MMPs）最近已被证明在感染幽门螺杆菌的胃上皮细胞中上调，可能有助于消化性溃疡的发病机制。本研究的目的是扩展关于幽门螺杆菌感染对胃上皮细胞MMP-1表达的影响、诱导动力学、细菌的致病特性以及MMP-1上调所需的细胞内信号通路的认识。AGS+细胞与携带致病岛（PAI）的幽门螺杆菌菌株共培养可使MMP-1的表达诱导增加10倍以上。PAI有突变且IV型分泌系统有缺陷的幽门螺杆菌菌株对MMP-1没有影响。双重免疫荧光显示，在细菌附着部位的胃活检上皮细胞中有强烈的MMP-1染色。在体外，MMP-1可被白细胞介素-1β和肿瘤坏死因子-α上调，但如抑制性抗体所示，这些调节机制在幽门螺杆菌感染中不起作用。发现JNK激酶和ERK1/2激酶的特异性抑制剂可抑制幽门螺杆菌诱导的MMP-1表达和活性。用反义MMP-1处理的AGS细胞降解重组基底膜的能力显著降低。我们的结果表明，在胃上皮细胞中，幽门螺杆菌通过JNK和ERK1/2以IV型分泌系统依赖性方式上调MMP-1。MMP-1的诱导进一步涉及幽门螺杆菌诱导的复杂过程，导致胃黏膜组织降解和重塑。
