Involvement of α5β1-integrin and TNF-α in Staphylococcus aureus α-toxin-induced death of epithelial cells

Abstract

Staphylococcus aureus causes suppurative infections which are often associated with tissue destruction and cell death. In the present study, we investigated the molecular and cellular basis of S.aureus-induced apoptosis and death in a human lung epithelial cell line (A549). We found that staphylococcal α-toxin is an important mediator of cytotoxicity in these epithelial cells. Specifically, we found that downregulating α-toxin production eliminated the cytotoxicity of S.aureus, whereas the addition of α-toxin to the cell culture medium significantly increased cell death in a dose-dependent manner. Importantly, we found that α-toxin-mediated cell death may partially function through α5β1-integrin, because both the β1-integrin antibody and the ligand fibronectin inhibited the cytotoxicity of α-toxin. Furthermore, we found that the overexpression of the inflammatory cytokine interferon (TNF)-α is associated with α-toxin-induced cell death, because both the TNF-α release inhibitor and antibody effectively inhibited the cytotoxicity of α-toxin. In contrast, the cytotoxicity of α-toxin was enhanced by the inhibition of the MAPK p38 and NF-κB pathways. Taken together, our results suggest that the activation of the MAPK p38 and NF-κB pathways are stress responses for survival, rather than direct contributes to α-toxin-induced cell death, and that the interaction of α-toxin with α5β1-integrin and overproduction of TNF-α may contribute to destruction of epithelial cells during S.aureus infection. © 2007 The Authors; Journal compilation © 2007 Blackwell Publishing Ltd.