RT Journal Article SR Electronic T1 Effect of Erythromycin on Biological Activities Induced by Clostridium perfringens α-Toxin JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 934 OP 940 DO 10.1124/jpet.108.143677 VO 327 IS 3 A1 Masataka Oda A1 Atsushi Kihara A1 Hiroki Yoshioka A1 Yuki Saito A1 Naoyuki Watanabe A1 Kana Uoo A1 Masahiro Higashihara A1 Masahiro Nagahama A1 Naoki Koide A1 Takashi Yokochi A1 Jun Sakurai YR 2008 UL http://jpet.aspetjournals.org/content/327/3/934.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics