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Infection and Immunity, February 2003, p. 845-849, Vol. 71, No. 2
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.2.845-849.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Induction by Sphingomyelinase of Shiga Toxin Receptor and Shiga Toxin 2 Sensitivity in Human Microvascular Endothelial Cells

T. G. Obrig,^1* R. M. Seaner,¹ M. Bentz,¹ C. A. Lingwood,² B. Boyd,² A. Smith,³ and W. Narrow³

Department of Medicine/Nephrology, University of Virginia, Charlottesville, Virginia,¹ Department of Biochemistry, Hospital for Sick Children, Toronto, Ontario, Canada,² Department of Microbiology, School of Medicine, University of Rochester, Rochester, New York³

Received 13 September 2002/ Returned for modification 15 October 2002/ Accepted 1 November 2002

Shiga toxin-producing enterohemorrhagic Escherichia coli is the major cause of acute renal failure in young children. The interaction of Shiga toxins 1 and 2 (Stx1 and Stx2) with endothelial cells is an important step in the renal coagulation and thrombosis observed in hemolytic uremic syndrome. Previous studies have shown that bacterial lipopolysaccharide and host cytokines slowly sensitize endothelial cells to Shiga toxins. In the present study, bacterial neutral sphingomyelinase (SMase) rapidly (1 h) sensitized human dermal microvascular endothelial cells (HDMEC) to the cytotoxic action of Stx2. Exposure of endothelial cells to neutral SMase (0.067 U/ml) caused a rapid increase of intracellular ceramide that persisted for hours. Closely following the change in ceramide level was an increase in the expression of globotriaosylceramide (Gb3), the receptor for Stx2. A rapid increase was also observed in the mRNA for ceramide:glucosyltransferase (CGT), the first of three glycosyltransferase enzymes of the Gb3 biosynthetic pathway. The product of CGT (glucosylceramide) was also increased. In contrast, mRNA for the third enzyme of the pathway, Gb3 synthase, was constitutively produced and was not influenced by SMase treatment of HDMEC. These results describe a rapid response mechanism by which extracellular neutral SMase derived from either bacteria or eukaryotic cells may signal endothelial cells to become sensitive to Shiga toxins.

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* Corresponding author. Mailing address: Department of Internal Medicine/Nephrology, Box 800133, University of Virginia, Charlottesville, VA 22908. Phone: (434) 982-1063. Fax: (434) 924-5848. E-mail: to3e{at}virginia.edu.

Editor: D. L. Burns

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Infection and Immunity, February 2003, p. 845-849, Vol. 71, No. 2
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.2.845-849.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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