Role of glucocorticoids in the response of the hypothalamo-corticotrope, immune and adipose systems to repeated endotoxin administration

The present study was designed to determine whether the glucocorticoid inhi bitory feedback mechanism plays a role in the well-known tolerance of the n euroendocrine-immune axis response to repeated endotoxemia. Adult male rats underwent adrenalectomy (ADX) and were implanted with a subcutaneous corti costerone (compound B, CB, 75 mg) pellet, or sham operated and implanted wi th a placebo pellet. On the morning of day 8 after surgery (experimental da y, D1), all rats received an intravenous injection of lipopolysaccharide (L PS) (25 mu g/kg body weight) which was repeated daily until D5. Blood was d rawn via intravenous indwelling catheters before (sample time zero) as well as 1, 2, 3 and 4 h after LPS treatment on D1, 3 and 5 for measurements of corticotropin (ACTH), CB, tumor necrosis factor-alpha (TNF-alpha) and lepti n. In sham animals, tolerance to repeated LPS administration was complete b y D5 for the corticotrope axis and the immune response. In addition, LPS wa s found to stimulate leptin secretion on day 1 in intact rats, an effect th at also disappeared thereafter. ADX + CB rats showed only a partial toleran ce of the corticotrope axis on D5, whereas tolerance of the immune response was similar to that found in sham animals. Interestingly, the acute stimul ation of leptin secretion by LPS in ADX + CB rats was qualitatively similar to that of intact controls on D1, but plasma leptin levels were significan tly reduced on D3 and 5 compared to controls. Our results demonstrate that the adrenal response tolerance of the hypothalamo-pituitary-adrenal axis to repeated endotoxemia. In addition, our finding that TNF-alpha secretion fo llows the same pattern in sham-operated and in adrenalectomized animals sug gests that unlike the corticotrope axis, tolerance of the immune response d oes not depend upon stimulated CB levels. The decrease in circulating level s of leptin following ADX is consistent with the stimulatory effects of glu cocorticoids on leptin secretion. However, our finding of an acute stimulat ion of leptin secretion by LPS in ADX + CB animals demonstrates that this e ffect of endotoxemia is at least partially glucocorticoid independent.