Pretreatment of mice with lipopolysaccharide (LPS) or IL-1β exerts dose-dependent opposite effects on Shiga toxin-2 lethality

Abstract

SUMMARYHaemolytic uraemic syndrome (HUS) has been closely associated with infection with a group of Shiga toxin-producing enterohaemorrhagic Eschericchia coli in young children. Shiga toxins (Stx) have been implicated as pathogenic agents of HUS by binding to the surface receptor of endothelial cells. LPS is a central product of the Gram-negative bacteria and several reports have documented that both LPS and Stx are important for disease development. In this study the reciprocal interactions between LPS and Stx2 are analysed in a mouse model. The results demonstrated that LPS was able to reduce or enhance Stx2 toxicity, depending on the dose and the timing of the injection. The involvement of the main early cytokines induced by LPS, tumour necrosis factor alpha (TNF-a) and IL-1b, in those LPS opposite effects on Stx2 toxicity was evaluated. Stx2 toxicity was enhanced by in vivo injection of murine TNF-a and low doses of murine IL-1b. However, at higher doses of IL-1b which induced corticosteroid increase in serum, Stx2 lethality was decreased. Considering that dexamethasone and IL-1b reproduce the LPS protective effects, it is suggested that endogenous corticosteroids secondary to the inflammatory response induced by LPS, mediate the protection against Stx2. It can be concluded that the fine equilibrium between proinflammatory and anti-inflammatory activities strongly influences Stx2 toxicity.

Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products

“…Survival rates of BALB/c mice from Shiga toxin 2 were enhanced by 18-h pretreatment of either LPS or dexamethasone whereas only 1 h of LPS pretreatment decreased survival rates. This protection afforded by the 18 h LPS pretreatment condition was shown to be due to the increased endogenous corticosterone production secondary to LPS-induced IL-1 activation of the HPA axis (Palermo et al 2000). In these studies, the role of endogenous glucocorticoids in protection against Shiga toxin lethality was further supported by the decreased survival of adrenalectomized animals or those treated with the GR antagonist RU486.…”

Shiga Toxin 2 Targets the Murine Renal Collecting Duct Epithelium

“…It has previously been shown that Stx2 causes renal failure in mice (3,33,47). Having demonstrated that Stx2 does not directly affect the murine renal glomerular filtration barrier cells in vitro, we sought to determine the Stx2 target cells in the mouse kidney.…”

Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome

“…These studies indicate a synergistic effect of Stx and LPS in vivo, as has also been shown in vitro using endothelial cells (68). Other reports observed that pretreatment with LPS could either increase or decrease Stx2-induced lethality, depending on the dose and timing of injection and that the effects could be modulated by TNF-␣ or IL-1␤ (97). A recent publication (98) showed that antibodies to LPS block adherence of STEC to human intestinal epithelial cells in vitro, although the biologic significance of this finding has not been evaluated in vivo.…”