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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan (M.O., A.K., H.Y., Y.S., N.W., K.U., M.H., M.N., J.S.); and Department of Microbiology and Immunology, Aichi Medical University, School of Medicine, Nagakute, Aichi, Japan (N.K., T.Y.)

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

Address correspondence to: Dr. Jun Sakurai, Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashirocho, Tokushima 770-8514, Japan. E-mail: sakurai{at}ph.bunri-u.ac.jp