title: Prevention of Clostridium sordellii lethal toxin-induced apoptotic cell death by tauroursodeoxycholic acid.
abstract: Virulent strains of Clostridium sordellii cause gangrenous myonecrosis in humans. The released lethal toxin (TcsL) and hemorrhagic toxin (TcsH) are regarded as the major virulence factors. TcsL inactivates low molecular weight GTP-binding proteins of the Rho/Ras subfamilies by monoglucosylation. In cultured cell lines, glucosylation, i.e., inactivation of Rho/Ras proteins, results in actin reorganization ("cytopathic effect") and apoptotic cell death ("cytotoxic effect"). Apoptotic cell death induced by TcsL is suggested to be based on inhibition of the phosphoinositide 3-kinase (PI3K)/Akt-survival pathway. In this study, we analyze the critical role of PI3K/Akt signaling in TcsL-induced apoptosis using the antiapoptotic bile acid tauroursodeoxycholic acid (TUDCA) as the pharmacological tool. TUDCA preserved the TcsL-induced decrease of the cellular level of phospho-Akt, suggesting that TUDCA activated PI3K/Akt signaling downstream of inhibited Ras signaling. TcsL-induced apoptosis was prevented by TUDCA treatment. The antiapoptotic effect of TUDCA was abolished by the PI3K inhibitor LY294002 and the Akt inhibitor, showing that the antiapoptotic effect depends on PI3K/Akt signaling. Inhibition of Ras/Rho signaling by TcsL resulted in activation of p38 MAP kinase. Inhibition of p38 MAP kinase by SB203580 protected cells from TcsL-induced apoptosis. TUDCA induced activation of p38 MAP kinase as well, an aspect of the TUDCA effects that most likely did not contribute to its antiapoptotic activity. Due to its antiapoptotic activity, TUDCA is under investigation for its potential application as a therapeutic modulator of apoptosis-related diseases. TUDCA may represent a new concept for the treatment of disease associated with toxigenic C. sordellii.
authors.affiliation: Institut für Toxikologie, Medizinische Hochschule Hannover, D-30625 Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Schulz
authors.forename: Ingo
authors.initials: I
authors.lastname: Just
authors.forename: Harald
authors.initials: H
authors.lastname: Genth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D003015:Clostridium Infections / Q000188:drug therapy; D047989:Paraclostridium sordellii / Q000472:pathogenicity*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors
chemical_list: D001427:Bacterial Toxins; D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; C072292:lethal toxin LT, Clostridium sordellii; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; C093642:SB 203580