Journal
MICROBIAL PATHOGENESIS
Volume 36, Issue 4, Pages 189-196Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.micpath.2003.11.004
Keywords
Escherichia coli; Shiga toxin; hemolytic uremic syndrome; brain endothelial cells; cytokines
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Funding
- NIA NIH HHS [AG13846] Funding Source: Medline
- NIDDK NIH HHS [DK34928, DK59811, DK52122] Funding Source: Medline
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Infection with Shiga toxin (Stx)-producing Escherichia coli can lead to development of hemolytic uremic syndrome (HUS). Patients with severe HUS often exhibit central nervous system (CNS) pathology, which is thought to involve damage to brain endothelium, a component of the blood-brain barrier. We hypothesized that this neuropathology occurs when cerebral endothelial cells of the blood-brain barrier, sensitized by exogenous TNF-alpha and stimulated by Stx1, produce and release proinflammatory cytokines. This was tested by measuring changes in cytokine mRNA and protein expression in human brain endothelial cells (hBEC) in vitro when challenged by TNF-alpha and/or Six. High doses of Stx1 alone were somewhat cytotoxic to hBEC; Six1-treated cells produced increased amounts of IL-6 mRNA and secreted this cytokine. IL-1beta and TNF-alpha mRNA, but not protein, were increased, and IL-8 secretion increased without an observed increase in mRNA. Cells pretreated with TNF-alpha were more sensitive to Stx1, displaying greater Stx1-induction of mRNA for TNF-alpha, IL-1beta, and IL-6, and secretion of IL-6 and IL-8. These observations suggest that in the pathogenesis of HUS, Six can induce cytokine release from hBEC, which may contribute toward the characteristic CNS neuropathology. (C) 2004 Published by Elsevier Ltd.
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