Effect of Erythromycin on Biological Activities Induced by Clostridium perfringens α-Toxin

Clostridium perfringens α-toxin, an important agent of gas gangrene with inflammatory myopathies, possesses lethal, hemolytic, and necrotic activities. Here, we show that α-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)-α, interleukin (IL)-1β, and IL-6 and systemic hemolysis induced by α-toxin, whereas the administration of kitasamycin did not. Furthermore, the lethality and systemic hemolysis caused by α-toxin were blocked by the preinjection of anti-TNF-α, but not the anti-IL-1β- or anti-IL-6-antibody. In addition, TNF-α-deficient mice were resistant to α-toxin, indicating that TNF-α plays an important role in the lethality. ERM inhibited the toxin-induced release of TNF-α 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-α from neutrophils. The observation shows that the toxin-induced release of TNF-α 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.