Abstract
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.
Footnotes
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This study was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; by the Open Research Center Fund for Promotion; and by the Mutual Aid Corporation for School of Japan.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.143677.
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ABBREVIATIONS: IL, interleukin; PAF, platelet-activating factor; TNF, tumor necrosis factor; DG, diacylglycerol; ERM, erythromycin; KTM, kitasamycin; PD98059, 2′-amino-3′-methoxyflavone; PT, pertussis toxin; ERK, extracellular-regulated kinase; IFN, interferon; ELISA, enzyme-linked immunosorbent assay; MCLA, 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo(1,2-a)pyrazin-3-one; TrkA, toropomyosin-related kinase receptor A.
- Received July 20, 2008.
- Accepted September 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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