SHIGA TOXIN-ASSOCIATED HEMOLYTIC-UREMIC SYNDROME - INTERLEUKIN-1-BETA ENHANCEMENT OF SHIGA TOXIN CYTOTOXICITY TOWARD HUMAN VASCULAR ENDOTHELIAL-CELLS IN-VITRO

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-1beta (IL-1beta) enhances the cytotoxic potency of Shiga toxin toward HUVEC. A preincubation of HUVEC with IL-1beta is required for sensitization of HUVEC to Shiga toxin. Sensitization of HUVEC to Ship toxin is IL-1beta dose dependent. Development of the IL-1beta response is time dependent, beginning within 2 h of IL-1beta preincubation and increasing over the next 24 h. That these responses were due to IL-1beta was demonstrated by heat inactivation of IL-1beta, by neutralization of IL-1beta by specific antibody, and by the ability of an IL-1beta receptor antagonist to inhibit the effect of IL-1beta. Shiga toxin-related inhibition of HUVEC protein synthesis preceded loss of cell viability. IL-1beta incubation with HUVEC induced the receptor for Shiga toxin, globotriaosylceramide. Lipopolysaccharide included during IL-1beta preincubation with HUVEC increased sensitivity to Shiga toxin in an additive manner. We conclude that IL-1beta may induce Shiga toxin sensitivity in endothelial cells and contribute to the development of HUS.