Differential role of glucocorticoids in mediating endotoxin-induced changes in IGF-I and IGFBP-1

The purpose of the present study was to determine whether endogenous elevations in glucocorticoids mediate the changes in insulin-like growth factor (IGF) I and IGF binding protein (IGFBP) 1 levels in plasma and tissues observed after in vivo administration of lipopolysaccharide (LPS). In overnightfasted male rats LPS injected via the tail vein decreased the IGF-I concentration in plasma, liver, and skeletal muscle (30-45%) and increased IGF-I content in kidney (∼3-fold). LPS also decreased IGF-I mRNA abundance in liver and muscle and increased gene expression in kidney. Concomitantly, IGFBP-1 levels in plasma, liver, and muscle were markedly elevated by LPS. All these changes were associated with a greater than fourfold elevation in plasma corticosterone. Pretreatment of rats with the glucocorticoid receptor antagonist RU-486 completely prevented or blunted the LPS-induced changes in IGF-I content in plasma, liver, muscle, and kidney. In liver and muscle RU-486 significantly attenuated the reduction in IGF-I mRNA abundance produced by LPS, but in kidney the LPS-induced increase in IGF-I mRNA was still evident. In contrast, pretreatment with RU-486 did not prevent or attenuate the LPS-induced increase in IGFBP-1 levels in plasma, liver, or muscle. These data suggest that glucocorticoids play a major role in regulating IGF-I mRNA and peptide content in tissues in response to LPS, but the increased IGFBP-1 in blood and tissues induced by LPS appears largely glucocorticoid independent.