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

Development of hemolytic uremic syndrome (HUS) after infection by Shig ella dysenteriae 1 or enterohemorrhagic Escherichia coli has been asso ciated 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 endotheli al cells (HUVEC) with interleukin-1beta (IL-1beta) enhances the cytoto xic potency of Shiga toxin toward HUVEC. A preincubation of HUVEC with IL-1beta is required for sensitization of HUVEC to Shiga toxin. Sensi tization of HUVEC to Ship toxin is IL-1beta dose dependent. Developmen t 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 r esponses 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 o f IL-1beta. Shiga toxin-related inhibition of HUVEC protein synthesis preceded loss of cell viability. IL-1beta incubation with HUVEC induce d the receptor for Shiga toxin, globotriaosylceramide. Lipopolysacchar ide included during IL-1beta preincubation with HUVEC increased sensit ivity 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.