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Infection and Immunity, May 2006, p. 2876-2886, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2876-2886.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Signal Transduction Mechanism Involved in Clostridium perfringens Alpha-Toxin-Induced Superoxide Anion Generation in Rabbit Neutrophils

Masataka Oda, Syusuke Ikari, Takayuki Matsuno, Yuka Morimune, Masahiro Nagahama, and Jun Sakurai*

Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan

Received 25 September 2005/ Returned for modification 29 November 2005/ Accepted 17 February 2006

Clostridium perfringens alpha-toxin induces the generation of superoxide anion (O2–) via production of 1,2-diacylglycerol (DG) in rabbit neutrophils. The mechanism of the generation, however, remains poorly understood. Here we report a novel mechanism for the toxin-induced production of O2– in rabbit neutrophils. Treatment of the cells with the toxin resulted in tyrosine phosphorylation of a protein of about 140 kDa. The protein reacted with anti-TrkA (nerve growth factor high-affinity receptor) antibody and bound nerve growth factor. Anti-TrkA antibody inhibited the production of O2– and binding of the toxin to the protein. The toxin induced phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDK1). K252a, an inhibitor of TrkA receptor, and LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), reduced the toxin-induced production of O2– and phosphorylation of PDK1, but not the formation of DG. These inhibitors inhibited the toxin-induced phosphorylation of protein kinase C {theta} (PKC{theta}). U73122, a phospholipase C (PLC) inhibitor, and pertussis toxin inhibited the toxin-induced generation of O2– and formation of DG, but not the phosphorylation of PDK1. These observations show that the toxin independently induces production of DG through activation of endogenous PLC and phosphorylation of PDK1 via the TrkA receptor signaling pathway and that these events synergistically activate PKC{theta} in stimulating an increase in O2–. In addition, we show the participation of mitogen-activated protein kinase-associated signaling events via activation of PKC{theta} in the toxin-induced generation of O2–.

* Corresponding author. Mailing address: Faculty of Pharmaceutical Sciences, Department of Microbiology, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan. Phone: 81-088-622-9611. Fax: 81-088-655-3051. E-mail: sakurai{at}ph.bunri-u.ac.jp.

Editor: V. J. DiRita

Infection and Immunity, May 2006, p. 2876-2886, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2876-2886.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Oda, M., Kihara, A., Yoshioka, H., Saito, Y., Watanabe, N., Uoo, K., Higashihara, M., Nagahama, M., Koide, N., Yokochi, T., Sakurai, J. (2008). Effect of Erythromycin on Biological Activities Induced by Clostridium perfringens {alpha}-Toxin. J. Pharmacol. Exp. Ther. 327: 934-940 [Abstract] [Full Text]  
  • Oda, M., Matsuno, T., Shiihara, R., Ochi, S., Yamauchi, R., Saito, Y., Imagawa, H., Nagahama, M., Nishizawa, M., Sakurai, J. (2008). The relationship between the metabolism of sphingomyelin species and the hemolysis of sheep erythrocytes induced by Clostridium perfringens {alpha}-toxin. J. Lipid Res. 49: 1039-1047 [Abstract] [Full Text]  


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