Involvement of alpha5beta1-integrin and TNF-alpha in Staphylococcus aureus alpha-toxin-induced death of epithelial cells.
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 alpha-toxin is an important mediator of cytotoxicity in these epithelial cells. Specifically, we found that downregulating alpha-toxin production eliminated the cytotoxicity of S. aureus, whereas the addition of alpha-toxin to the cell culture medium significantly increased cell death in a dose-dependent manner. Importantly, we found that alpha-toxin-mediated cell death may partially function through alpha5beta1-integrin, because both the beta1-integrin antibody and the ligand fibronectin inhibited the cytotoxicity of alpha-toxin. Furthermore, we found that the overexpression of the inflammatory cytokine interferon (TNF)-alpha is associated with alpha-toxin-induced cell death, because both the TNF-alpha release inhibitor and antibody effectively inhibited the cytotoxicity of alpha-toxin. In contrast, the cytotoxicity of alpha-toxin was enhanced by the inhibition of the MAPK p38 and NF-kappaB pathways. Taken together, our results suggest that the activation of the MAPK p38 and NF-kappaB pathways are stress responses for survival, rather than direct contributes to alpha-toxin-induced cell death, and that the interaction of alpha-toxin with alpha5beta1-integrin and overproduction of TNF-alpha may contribute to destruction of epithelial cells during S. aureus infection.
Liang
Xudong
X
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota. 1971 Commonwealth Ave. St Paul, MN 55108, USA.
Ji
Yinduo
Y
D017209:Apoptosis / Q000187:drug effects*; D001427:Bacterial Toxins / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology* / Q000502:physiology; D015964:Gene Expression Regulation, Bacterial; D006460:Hemolysin Proteins / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000378:metabolism / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D039081:Integrin alpha5beta1; D014409:Tumor Necrosis Factor-alpha; C021091:staphylococcal alpha-toxin