NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver

Abstract

Priego, Teresa, Inmaculada Ibáñez de Cáceres, Ana Isabel Martín, M. Á ngeles Villanú a, and Asunción López-Calderón. NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver. Am J Physiol Endocrinol Metab 286: E50-E56, 2004. First published September 16, 2003 10.1152/ajpendo.00149.2003In this study, we administered aminoguanidine, a relatively selective inducible nitric oxide synthase (iNOS) inhibitor, to study the role of nitric oxide (NO) in LPSinduced decrease in IGF-I and IGFBP-3. Adult male Wistar rats were injected intraperitoneally with LPS (100 g/kg), aminoguanidine (100 mg/kg), LPS plus aminoguanidine, or saline. Rats were injected at 1730 and 0830 the next day and killed 4 h after the last injection. LPS administration induced an increase in serum concentrations of nitrite/ nitrate (P Ͻ 0.01) and a decrease in serum concentrations of growth hormone (GH; P Ͻ 0.05) and IGF-I (P Ͻ 0.01) as well as in liver IGF-I mRNA levels (P Ͻ 0.05). The LPS-induced decrease in serum concentrations of IGF-I and liver IGF-I gene expression seems to be secondary to iNOS activation, since aminoguanidine administration prevented the effect of LPS on circulating IGF-I and its gene expression in the liver. In contrast, LPS-induced decrease in serum GH was not prevented by aminoguanidine administration. LPS injection decreased IGFBP-3 circulating levels (P Ͻ 0.05) and its hepatic gene expression (P Ͻ 0.01), but endotoxin did not modify the serum IGFBP-3 proteolysis rate. Aminoguanidine administration blocked the inhibitory effect of LPS on both IGFBP-3 serum levels and its hepatic mRNA levels. When aminoguanidine was administered alone, IGFBP-3 serum levels were increased (P Ͻ 0.05), whereas its hepatic mRNA levels were decreased. This contrast can be explained by the decrease (P Ͻ 0.05) in serum proteolysis of this binding protein caused by aminoguanidine. These data suggest that iNOS plays an important role in LPS-induced decrease in circulating IGF-I and IGFBP-3 by reducing IGF-I and IGFBP-3 gene expression in the liver. nitric oxide; inducible nitric oxide synthase; lipopolysaccharide; growth hormone; insulin-like growth factor I; insulin-like growth factor-binding protein-3; proteolysis; aminoguanidine SEPSIS INDUCES PROTEOLYSIS and negative nitrogen balance, which leads to lean body mass loss and cachexia. Sepsis is also associated with a wide range of hormonal changes that contribute to the catabolic state; among these there is an alteration of the somatotropic axis (47). A decrease in serum concentrations of IGF-I in septic patients and in different inflammatory diseases has also been observed (12,28).Lipopolysaccharide (LPS), or endotoxin, triggers the initiation of host responses to sepsis by gram-negative bacterial infection. Endotoxin administration in rats increases plasma concentrations of corticosterone, whereas it decreases circulating growth hormone (GH) and IGF-I (20, 27). The decrease in circulating IGF-I is secondary to a decrease in IGF-I gene expres...

Dexamethasone administration attenuates the inhibitory effect of lipopolysaccharide on IGF-I and IGF-binding protein-3 in adult rats

“…This effect might be due, in part, to the inhibitory effects of dexamethasone on NO production, since dexamethasone decreased the expression of iNOS in hepatocytes (Geller et al 1993). In addition, in the present study we found that dexamethasone pretreatment blocked the increase in circulating nitrite and nitrate concentrations in LPS-treated rats, and furthermore, we have shown that iNOS inhibition attenuated the inhibitory effect of LPS on hepatic IGFBP-3 mRNA levels (Priego et al 2004). …”

“…This mechanism could involve NO, since dexamethasone pretreatment prevents the increase in serum nitrite and nitrate concentrations in LPS-treated rats. Moreover, we have previously reported (Priego et al 2004) that inhibition of iNOS by aminoguanidine administration prevented the effect of LPS on circulating IGF-I and its gene expression in the liver as well as on circulating nitrite and nitrate concentrations.…”

“…Nitric oxide (NO) could be one of the possible inhibitory factors. We have observed that administration of an inducible NO synthase (iNOS) inhibitor prevented the increase in serum nitrites and nitrates as well as the decrease in both IGF-I and IGFBP-3 serum levels and their hepatic mRNA levels induced by LPS (Priego et al 2004). Furthermore, it has been reported that dexamethasone decreases hepatocyte iNOS mRNA levels in vitro (Geller et al 1993).…”

Inactivation of Kupffer cells by gadolinium administration prevents lipopolysaccharide-induced decrease in liver insulin-like growth factor-I and IGF-binding protein-3 gene expression

“…Thus the ability of gadolinium to prevent LPS-induced increase in serum concentrations of nitrite/nitrate can be the result of blocking iNOS induction in several tissues. We have previously observed that inhibition of iNOS by aminoguanidine treatment prevents LPS-induced decrease in IGF-I and IGFBP-3 gene expression in the liver (Priego et al 2004). Therefore, prevention of iNOS induction and nitric oxide release in the liver may be one of the possible mechanisms by which gadolinium administration prevents the effect of LPS on serum and liver IGF-I and IGFBP-3.…”

“…Induction of inducible nitric oxide synthase (iNOS) during sepsis is involved in the inhibition of IGF-I-IGFBP-3 after LPS administration (Priego et al 2004).…”