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 sufficien t for hemolytic uremic syndrome (HUS) development, and pro-inflammatory sti muli such as lipopolysaccharide (LPS) from Cram negative bacteria are neede d. Taking into account that LPS is present in the natural infection during HUS development, detoxification or regulation of LPS activity could be cruc ial 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-L PS antibodies in immunized mice did not modify the dual effects of LPS (enh ancement or protection) on Stx? action. This could be attributed to the fac t that antibodies do not recognize the active portion of LPS molecule (lipi d A). However, the enhancement of Stx2 toxicity exerted by LPS was inhibite d 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 cytokin es known to be involved in the overexpression of Stx receptors. The phenome non of LPS-induced protection on Stx2 toxicity was also inhibited in tolera nt animals, although the mechanism involved in this effect is not clear. Th is is the first description which shows the influence of endotoxin toleranc e on the evolution of experimental NUS. However, like in Gram negative infe ctions, further knowledge on tolerance mechanism is necessary in order to a chieve a comprehensive view of this phenomenon. (C) 2001 Elsevier Science B .V. All rights reserved.