We tested whether endotoxin (lipopolysaccharide, LPS) inhibits IGF-I gene expression in hepatocytes and the possible role of Kupffer cells and nitric oxide (NO) in this effect. LPS decreased IGF-I mRNA in hepatocyte cultures and increased the nitrite + nitrate levels in the culture medium. Furthermore, there was a negative correlation between the IGF-I mRNA and the nitrite+nitrate levels. When hepatocytes were cocultured with Kupffer cells, the inhibitory effect of LPS on IGF-I mRNA was higher than in hepatocyte cultures, but the stimulatory effect on nitrite+nitrate was similar in both conditions. The exogenous NO donated by S-nitroso-n-acetyl-d,l-penicillamide also decreased the IGF-I gene expression in hepatocyte cultures. In addition, two specific inducible NO synthase (iNOS) inhibitors, l-N6-(1-iminoethyl)lysine (l-NIL) and aminoguanidine, prevented the effect of LPS on nitrite+nitrate levels and on IGF-I gene expression in hepatocyte cultures. These data indicate that iNOS-derived NO may cause downregulation of IGF-I gene expression in hepatocytes. However, in cocultures, the iNOS inhibitor l-NIL prevented the effect of LPS on nitrite+nitrate levels, but only attenuated the LPS-induced decrease in IGF-I gene expression. We conclude that in hepatocytes, LPS-induced decrease in IGF-I is mainly due to induction of iNOS, whereas in the presence of Kupffer cells LPS inhibits IGF-I through NO release and through other inhibitory pathways.

The aim of this study was to investigate whether glucocorticoid administration had a beneficial effect on serum concentrations of insulin-like growth factor I (IGF-I) and on IGF-binding protein 3 (IGFBP-3) in rats injected with lipopolysaccharide (LPS). Adult male rats were injected with LPS or saline and pretreated with dexamethasone or saline. Dexamethasone administration decreased growth hormone (GH) receptor and IGF-I mRNA levels in the liver of control rats. LPS decreased GH receptor and IGF-I gene expression in the liver of saline-treated rats but not in the liver of dexamethasone-pretreated rats. In the kidney, GH receptor mRNA levels were not modified by dexamethasone or LPS treatment. However, LPS decreased renal IGF-I gene expression and dexamethasone pretreatment prevented this decrease. Serum concentrations of IGF-I were decreased by LPS, and dexamethasone pretreatment attenuated this effect. The gene expression of IGFBP-3 in the liver and kidney and its circulating levels were decreased by LPS. In control rats dexamethasone increased circulating IGFBP-3 and its gene expression in the liver, and decreased the proteolysis of this protein. Dexamethasone pretreatment attenuated the LPS-induced decrease in IGFBP-3 gene expression in the liver and prevented the LPS-induced decrease in IGFBP-3 gene expression in the kidney. Moreover, dexamethasone pretreatment attenuated the LPS-induced decrease in serum concentrations of IGFBP-3 and decreased the LPS-induced IGFBP-3 proteolysis in serum. In conclusion, dexamethasone pretreatment partially attenuates the inhibitory effect of LPS on serum IGF-I by blocking the decrease of its gene expression in the kidney as well as by attenuating the decrease in serum concentrations of IGFBP-3.