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Infect. Immun. doi:10.1128/IAI.01581-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Stx2 Causes Apoptosis In Human Brain Microvascular Endothelial Cells Via CHOP

Department of Bacteriology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan; Department of Internal Medicine/Nephrology, Center for Global Health, Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, U.S.A.; Discovery Research Laboratory, Shionogi & Co., Ltd, 2-5-1, Mishima Settsu-city, Osaka, 566-0022, Japan; Molecular Structure and Function, Research Institute, Hospital for Sick Children, 555 University Avenue Toronto, Ontario, M5G 1X8, Canada; Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

^* To whom correspondence should be addressed. Email: junfujii{at}bact.med.kyushu-u.ac.jp.

	Abstract

Shiga toxin 1 and 2 (Stxs) produced by Escherichia coli O157 is 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 caspases-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 up-regulation of C/EBP homologue protein/growth arrest (CHOP). 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.