Effect of glucocorticoids in the development of endotoxin tolerance

M. B. REARTE; V. LANDONI; P. CHIARELLA; E. LABORDE; M. F. LÓPEZ; G. C. FERNÁNDEZ; M. A. ISTURIZ

Rio de Janeiro, Brasil

Congreso; 13th International Congress of Immunology; 2007

Repeated exposure to small doses of lipopolysaccharide (LPS) induce a state of hyporesponsiveness to a subsequent challenge with LPS.This phenomenon, termed  endotoxin or LPS tolerance, remains poorly understood. This hyporesponsiveness observed in sepsis and systemic inflammatory response syndromes is frequently associated to immunesuppression. Glucocorticoids (GC) have been studied in the management of these events. However, while some authors said that GC are not involved (J Infect Dis 2004; 189:1295), others said that are essential (PNAS 1994; 91:271). In this report we study the effects of GC in the development and maintenance of LPS tolerance. For this purpose, two groups of 5 BALB/c mice were tolerized with LPS (0.08mg/Kg i.p., E. coli O111:B4, during 5 days). Five minutes before the lethal dose of LPS (8mg/Kg) injection, one of the groups was s.c. injected with 0.3mg of RU486, an antagonist of GC receptors. The mortality was: Tolerants 0/5; Tolerants+RU486 5/5; naïve mice+LPS 5/5 (n=4). However, when LPS was injected 7h after RU486 all the animals survived. These results indicate that RU486 generates a transient breakdown in the tolerance to LPS, suggesting the importance of GC. In addition, when dexamethasone (2.5 mg/Kg, i.p.) was injected simultaneously with lethal LPS, the animals survived (5/5). Administered 7h before LPS, the survival was lower (1/5) (n=4). The mortality correlates with higher levels of TNF in plasma. Moreover, dexamethasone prevents LPS-induced tolerization, while RU486 did not. These data reveal a role of GC in our model, either in the maintenance or in the development of LPS tolerance.