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Mechanism of Clostridium difficile Toxin A–Induced Apoptosis in T84 Cells

2002; Oxford University Press; Volume: 186; Issue: 10 Linguagem: Inglês

10.1086/344729

1537-6613

Gerly Anne de Castro Brito, Jun Fujji, Benedito A. Carneiro‐Filho, Aldo Â. M. Lima, Tom G. Obrig, Richard L. Guerrant,

Antimicrobial Resistance in Staphylococcus

This study is an investigation into the mechanism of Clostridium difficile toxin A-induced apoptosis in human intestinal epithelial cells. Toxin A induced apoptosis of T84 cells in a dose- and time-dependent fashion. Toxin A-induced apoptosis was completely inhibited by blocking toxin enzymatic activity on Rho GTPases with uridine 5'-diphosphate-2',3'-dialdehyde by a nonspecific caspase inhibitor and was partially inhibited by caspase-1, -3, -6, -8, and -9 inhibitors. Caspases 3, 6, 8, and 9 and Bid activation were detected. Toxin A also induced changes in mitochondrial membrane potential and cytochrome c release at 18-24 h, a time course similar to caspase-9 activation. In conclusion, toxin A induces apoptosis by a mechanism dependent on inactivation of Rho, activation of caspases 3, 6, 8, and 9 and Bid, and mitochondrial damage followed by cytochrome c release. Toxin A proapoptotic activity may contribute to the mucosal disruption seen in toxin A-induced enteritis.