title: The p38 MAPK and JNK pathways protect host cells against Clostridium perfringens beta-toxin.
abstract: Clostridium perfringens beta-toxin is an important agent of necrotic enteritis and enterotoxemia. Beta-toxin is a pore-forming toxin (PFT) that causes cytotoxicity. Two mitogen-activated protein kinase (MAPK) pathways (p38 and c-Jun N-terminal kinase [JNK]-like) provide cellular defense against various stresses. To investigate the role of the MAPK pathways in the toxic effect of beta-toxin, we examined cytotoxicity in five cell lines. Beta-toxin induced cytotoxicity in cells in the following order: THP-1 = U937 > HL-60 > BALL-1 = MOLT-4. In THP-1 cells, beta-toxin formed oligomers on lipid rafts in membranes and induced the efflux of K(+) from THP-1 cells in a dose- and time-dependent manner. The phosphorylation of p38 MAPK and JNK occurred in response to an attack by beta-toxin. p38 MAPK (SB203580) and JNK (SP600125) inhibitors enhanced toxin-induced cell death. Incubation in K(+)-free medium intensified p38 MAPK activation and cell death induced by the toxin, while incubation in K(+)-high medium prevented those effects. While streptolysin O (SLO) reportedly activates p38 MAPK via reactive oxygen species (ROS), we showed that this pathway did not play a major role in p38 phosphorylation in beta-toxin-treated cells. Therefore, we propose that beta-toxin induces activation of the MAPK pathway to promote host cell survival.
authors.affiliation: Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagahama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibutani
authors.forename: Soshi
authors.initials: S
authors.lastname: Seike
authors.forename: Mami
authors.initials: M
authors.lastname: Yonezaki
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Takagishi
authors.forename: Masataka
authors.initials: M
authors.lastname: Oda
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Jun
authors.initials: J
authors.lastname: Sakurai
mesh_terms: D001427:Bacterial Toxins / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003016:Clostridium perfringens / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; C031884:CPB protein, Clostridium perfringens; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases