Clostridium difficile toxin B activates the EGF receptor and the ERK/MAP kinase pathway in human colonocytes.
BACKGROUND & AIMS: Clostridium difficile toxin B (TxB) mediates acute inflammatory diarrhea characterized by neutrophil infiltration and intestinal mucosal injury. In a xenograft animal model, TxB was shown to induce interleukin (IL)-8 gene expression in human colonic epithelium. However, the precise mechanisms of this TxB response are unknown. The aim of this study was to investigate the TxB-mediated proinflammatory pathway in colonocytes. METHODS: The effect of TxB on epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK) 1/2 signaling pathway and IL-8 gene expression was assessed in nontransformed human colonic epithelial NCM460 cells. TxB regulation of EGFR-ERK1/2 signaling pathways was determined using immunoblot analysis, confocal microscopy, and enzyme-linked immunosorbent assay, whereas IL-8 gene expression was measured by luciferase promoter assay. RESULTS: TxB activates EGFR and ERK1/2 phosphorylation with subsequent release of IL-8 from human colonocytes. Pretreatment with either the EGFR tyrosine kinase inhibitor, AG1478, or an EGFR-neutralizing antibody blocked both TxB- induced EGFR and ERK activation. By using neutralizing antibodies against known ligands of EGFR, we found that the activation of EGFR and ERK1/2 phosphorylation was mediated by transforming growth factor-alpha (TGF-alpha). Inhibition of matrix metalloproteinase (MMP) decreased TGF-alpha secretion and TxB- induced EGFR and ERK activation. Inhibition of MMP, EGFR, and ERK activation significantly decreased TxB- induced IL-8 expression. CONCLUSIONS: TxB signals acute proinflammatory responses in colonocytes by transactivation of the EGFR and activation of the ERK/MAP kinase pathway.[1]References
- Clostridium difficile toxin B activates the EGF receptor and the ERK/MAP kinase pathway in human colonocytes. Na, X., Zhao, D., Koon, H.W., Kim, H., Husmark, J., Moyer, M.P., Pothoulakis, C., LaMont, J.T. Gastroenterology (2005) [Pubmed]
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