Interaction of Shiga Toxins with Human Brain Microvascular Endothelial Cells: Cytokines as Sensitizing Agents

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Abstract
Neurologic abnormalities are among the most serious extraintestinal complications of infection with Shiga toxin (Stx)-producing bacteria. Histopathologic examination of tissues from patients with extraintestinal sequelae suggested that Stxs damage endothelial cells. It is shown here that human brain microvascular endothelial cells (HBMECs) are relatively resistant to purified Stxs (50% cytotoxic doses [CD50s] ⩾10 μg/mL). Pretreatment of HBMECs with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, n-butyric acid, or a cAMP analogue resulted in a 103- to 104-fold decrease in CD50 values and a 2- to 4-fold increase in fluoresceinated Stx binding to HBMECs. Treatment of HBMECs with lipopolysaccharides did not significantly alter cytotoxicity or toxin binding. TNF-α and IL-1β treatment was associated with the increased HBMEC expression of the toxin-binding glycolipid globotriaosylceramide. HBMECs did not produce IL-1β and produced only trace amounts of TNF-α when stimulated with purified Stxl in vitro.

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