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Infection and Immunity, August 2008, p. 3679-3689, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.01581-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Shiga Toxin 2 Causes Apoptosis in Human Brain Microvascular Endothelial Cells via C/EBP Homologous Protein{triangledown}

Jun Fujii,1* Katie Wood,2 Fumiko Matsuda,1 Benedito A. Carneiro-Filho,3 Keilo H. Schlegel,2 Takashi Yutsudo,4 Beth Binnington-Boyd,5 Clifford A. Lingwood,5 Fumiko Obata,2 Kwang S. Kim,6 Shin-ichi Yoshida,1 and Tom Obrig2

Department of Bacteriology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan,1 Department of Internal Medicine/Nephrology,2 Center for Global Health, Department of Medicine, University of Virginia, Charlottesville, Virginia 22908,3 Discovery Research Laboratory, Shionogi & Co., Ltd., 2-5-1, Mishima Settsu City, Osaka 566-0022, Japan,4 Molecular Structure and Function Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada,5 Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland 212876

Received 30 November 2007/ Returned for modification 8 January 2008/ Accepted 28 May 2008

Shiga toxin 1 (Stx1) and Stx2 produced by Escherichia coli O157 are known to be cytotoxic to Vero and HeLa cells by inhibiting protein synthesis and by inducing apoptosis. In the present study, we have demonstrated that 10 ng/ml Stx2 induced DNA fragmentation in human brain microvascular endothelial cells (HBMEC), with cleavage activation of caspase-3, -6, -8, and -9. A microarray approach used to search for apoptotic potential signals in response to Stx2 revealed that Stx2 treatment induced a marked upregulation of C/EBP homologous protein (CHOP)/growth arrest and DNA damage-inducible protein 153 (GADD153). Increased CHOP expression was dependent on enzymatically active Stx1. Knockdown of CHOP mRNA reduced the activation of caspase-3 and prevented apoptotic cell death. These results suggest that Stx2-induced apoptosis is mediated by CHOP in HBMEC and involves activation of both the intrinsic and extrinsic pathways of apoptosis.

* Corresponding author. Mailing address: Department of Bacteriology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. Phone: 81-92-642-6130. Fax: 81-92-642-6129. E-mail: junfujii{at}bact.med.kyushu-u.ac.jp

{triangledown} Published ahead of print on 9 June 2008.

Editor: B. A. McCormick

Infection and Immunity, August 2008, p. 3679-3689, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.01581-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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