title: Effect of erythromycin on biological activities induced by clostridium perfringens alpha-toxin.
abstract: Clostridium perfringens alpha-toxin, an important agent of gas gangrene with inflammatory myopathies, possesses lethal, hemolytic, and necrotic activities. Here, we show that alpha-toxin-induced lethality in mice was inhibited by i.v. preadministration of erythromycin (ERM). Administration of ERM resulted in a drastic reduction in the release of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 and systemic hemolysis induced by alpha-toxin, whereas the administration of kitasamycin did not. Furthermore, the lethality and systemic hemolysis caused by alpha-toxin were blocked by the preinjection of anti-TNF-alpha, but not the anti-IL-1beta- or anti-IL-6-antibody. In addition, TNF-alpha-deficient mice were resistant to alpha-toxin, indicating that TNF-alpha plays an important role in the lethality. ERM inhibited the toxin-induced release of TNF-alpha from neutrophils and phosphorylation of toropomyosin-related kinase receptor A (TrkA) and extracellular-regulated kinase (ERK) 1/2. Furthermore, K252a, a TrkA inhibitor, and PD98059 (2'-amino-3'-methoxyflavone), an ERK1/2 inhibitor, inhibited the toxin-induced release of TNF-alpha from neutrophils. The observation shows that the toxin-induced release of TNF-alpha is dependent on the activation of ERK/mitogen-activated protein kinase signal transduction via TrkA in neutrophils and that ERM specifically blocks the toxin-induced events through the activation of neutrophils.
authors.affiliation: Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashirocho, Tokushima, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Oda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kihara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Yuki
authors.initials: Y
authors.lastname: Saito
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Kana
authors.initials: K
authors.lastname: Uoo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Higashihara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagahama
authors.forename: Naoki
authors.initials: N
authors.lastname: Koide
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
authors.forename: Jun
authors.initials: J
authors.lastname: Sakurai
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects; D004336:Drug Antagonism; D004917:Erythromycin / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects; D051379:Mice; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism; D010738:Type C Phospholipases / Q000494:pharmacology*
chemical_list: D000931:Antidotes; D001427:Bacterial Toxins; D002135:Calcium-Binding Proteins; D016207:Cytokines; D004917:Erythromycin; D010738:Type C Phospholipases; C040649:alpha toxin, Clostridium perfringens