Tolerance to lipopolysaccharide (LPS) regulates the endotoxin effects on Shiga toxin-2 lethality

it has been suggested that Shign toxin (Stx) is necessary but not sufficient for hemolytic uremic syndrome (HUS) development, and pro-inflammatory stimuli such as lipopolysaccharide (LPS) from Cram negative bacteria are needed. Taking into account that LPS is present in the natural infection during HUS development, detoxification or regulation of LPS activity could be crucial to define the course of the disease. The objective of the present study was to investigate whether tolerance to LPS and/or antibodies to LPS, are able to modify the LPS-induced modulation of Six type-2 (StxZ) lethality in a mouse model. Our results demonstrate that the high levels of IE:G anti-LPS antibodies in immunized mice did not modify the dual effects of LPS (enhancement or protection) on Stx? action. This could be attributed to the fact that antibodies do not recognize the active portion of LPS molecule (lipid A). However, the enhancement of Stx2 toxicity exerted by LPS was inhibited in tolerant mice. This effect could be ascribed to the inhibition of LPS-induced TNF-alpha. and IL-1 beta secretion in tolerant animals, two cytokines known to be involved in the overexpression of Stx receptors. The phenomenon of LPS-induced protection on Stx2 toxicity was also inhibited in tolerant animals, although the mechanism involved in this effect is not clear. This is the first description which shows the influence of endotoxin tolerance on the evolution of experimental NUS. However, like in Gram negative infections, further knowledge on tolerance mechanism is necessary in order to achieve a comprehensive view of this phenomenon. (C) 2001 Elsevier Science B.V. All rights reserved.