Involvement of intracellular signaling cascades in inflammatory responses in human intestinal epithelial cells following Vibrio cholerae infection

Vibrio cholerae, the etiological agent of cholera, leads to the induction of host cell nuclear responses and the activation of proinflammatory, cytokines in the cultured intestinal epithelial cells. However, the host cell signaling pathway leading to proinflammatory response is not explored. In this study, we demonstrated that V. cholerae infection on intestinal epithelial cells results in the activation of extracellular signal-regulated kinases1/2(ERK1/2) and p38 of the mitogen activated protein kinase (MAPK) family. V. cholerare induced intracellular pathways in Int407 cells leading to the activation of protein kinase A (PKA) and protein tyrosin kinase (PTK) in upstream of MAPK and nuclear factor-kappaB (NF-kappa B) pathway. Inhibitor study of Ca2+ and phospholipase-gamma (PLC-gamma) pathway suggested the possible involvement of Ca2+ signaling in the V. cholerae pathogenesis. V. cholerae culture supernatants as also insertional mutants of ctxA, toxR and toxT genes modulate the activation of MAPK and NF-kappa B signaling pathways. MAPK and NF-kappa B signaling pathway activation were also modulated by adherence and motility of V. cholerae. Studies with inhibitor of NF-kappa B, MAPK, PTK, PKA, PKC, Ca2+ and PLC pathways showed differential cytokine secretion in Int407 following V. cholerae infection. Therefore V. cholerae mediated induction of nuclear responses through signal transduction pathway and subsequent activation of proinflammatory cytokines in Int407 modulated by V. cholerae secretory factors, virulence, adhesion/motility which might explain some of its reactogenic mechanisms. (C) 2008 Elsevier Ltd. All rights reserved.