Effect of multiple cytokines plus bacterial endotoxin on glucose and nitric oxide production by cultured hepatocytes

Abstract

Treatment of cultured hepatocytes with a combination of cytokines, including tumour necrosis factor-alpha, interferon-gamma and interleukin-1 beta, plus lipopolysaccharide resulted in a time-dependent induction of nitric oxide (NO) synthase (as measured by NO2- (+) NO3- production) and inhibition of hepatic gluconeogenesis and glycogen breakdown. The inhibition of glucose release was comparable with the observed following treatment of rats with lipopolysaccharide or treatment of isolated hepatocytes with artificial NO donors. In addition, this effect was also evident with all substrates tested that enter the gluconeogenic pathway below the level of phosphoenolpyruvate carboxykinase, suggesting that this combination of cytokines may underlie the inhibition of gluconeogenesis observed in endotoxic shock. The maximal inhibition of glucose output required the presence of all the cytokines plus lipopolysaccharide, whereas the induction of NO synthase was independent of the lipopolysaccharide when the cytokines were employed. Inclusion of interferon-gamma was essential to obtain a maximal response for either parameter. Inclusion of 1 mM N(G)-monomethyl-L-arginine in the incubation abolished the increase in NO2- (+) NO3- observed with the complete cytokine mixture and various combinations; however, it failed to prevent the inhibition in glucose output, indicating that mechanisms other than NO underlie the cytokine-induced inhibition of glucose release.

AM3 inhibits LPS-induced iNOS expression in mice

“…We have previously found that AM3 inhibits LPS-induced TNF-a expression in peritoneal macrophages [14], which are a rich source of iNOS and contributes to NO accumulation during endotoxemia [17]. On the other hand, TNF-a up-regulation has been shown to induce iNOS expression [18], therefore the effect of AM3 on iNOS expression could be explained by its inhibitory effect on pro-inflammatory cytokines. Conversely, iNOS inhibitors down-regulate TNF-a synthesis [19].…”

Inducible nitric oxide synthase mediates cytokine release: The time course in conscious and septic rats

“…There were many reports to examine the effects of cytokines and NO after endotoxemia (Lee et al, 2002a;Moncada et al, 1991;ter Steege et al, 2000). The experiments were performed in anesthetized animals or various cell lines culture with only 4 -6 h of monitoring (Buttery et al, 1994;Ceppi et al, 1996;Liu et al, 1996;Mailman et al, 2001;Pedoto et al, 2002;Preiser et al, 2001;ter Steege et al, 2000). These situations were different from the clinical patients with endotoxemia.…”

The Role of Glucose in Brain Injury Following the Combination of Lipopolysaccharide or Lipoteichoic Acid and Hypoxia-Ischemia in Neonatal Rats

“…However, the possibility remains that LPS sensitizes the immature brain by lowering blood glucose, as LPS has previously been shown to reduce blood glucose levels through a decrease in gluconeogenesis and glycogenolysis [Goto et al, 1994;Ceppi et al, 1996]. In addition, acute lowering of blood glucose with insulin prior to HI increased brain injury, while a gradual lowering of glucose induced by fasting did not affect brain damage [Yager et al, 1992].…”