Shiga toxin-associated hemolytic uremic syndrome: Interleukin-1β enhancement of Shiga toxin cytotoxicity toward human vascular endothelial cells in vitro

Abstract

Development of hemolytic uremic syndrome (HUS) after infection by Shigella dysenteriae 1 or enterohemorrhagic Escherichia coli has been associated with the production of Shiga toxins (verotoxins). The putative target of Shiga toxins in HUS is the renal microvascular endothelium. This report shows that preincubation of human umbilical vein endothelial cells (HUVEC) with interleukin-1β (IL-1β) enhances the cytotoxic potency of Shiga toxin toward HUVEC. A preincubation of HUVEC with IL-1β is required for sensitization of HUVEC to Shiga toxin. Sensitization of HUVEC to Shiga toxin is IL-1β dose dependent. Development of the IL-1β response is time dependent, beginning within 2 h of IL-1β preincubation and increasing over the next 24 h. That these responses were due to IL-1β was demonstrated by heat inactivation of IL-1β, by neutralization of IL-1β by specific antibody, and by the ability of an IL-1β receptor antagonist to inhibit the effect of IL-1β. Shiga toxin-related inhibition of HUVEC protein synthesis preceded loss of cell viability. IL-1β incubation with HUVEC induced the receptor for Shiga toxin, globotriaosylceramide. Lipopolysaccharide included during IL-1β preincubation with HUVEC increased sensitivity to Shiga toxin in an additive manner. We conclude that IL-1β may induce Shiga toxin sensitivity in endothelial cells and contribute to the development of HUS.