Insulin-like growth factor 1 prevents liver injury through the inhibition of TNF-α and iNOS induction in D-galactosamine and LPS-treated rats

Insulin-like growth factor (IGF) 1 has protective effects in liver failure. However, the effect of IGF-1 on inflammatory mediators such as proinflammatory cytokines and NO remains to be clarified. We hypothesized that IGF-1 inhibited the induction of these cytokines and iNOS, resulting in beneficial effect in the liver. Rats were treated with D-galactosamine (400 mg kg) and LPS (16 μg kg) (GalN/LPS) to induce acute liver failure. Insulin-like growth factor 1 (3.2 mg kg) was administered subcutaneously before GalN/LPS injection. Insulin-like growth factor 1 increased the survival rate in GalN/LPS-treated rats and prevented the increases of transaminases and total bilirubin in serum. Histopathological analysis revealed that IGF-1 decreased the incidence of hepatic apoptosis and neutrophil infiltration. Insulin-like growth factor 1 inhibited increases in TNF-α, IL-1β, and cytokine-induced neutrophil chemoattractant 1 caused by GalN/LPS in serum and liver and enhanced serum IL-10. Insulin-like growth factor 1 reduced the induction of iNOS mRNA and its protein in GalN/LPS-treated liver and resulted in a decrease in NO production. However, IGF-1 had no effect on the activation of nuclear factor-κB. Analysis of iNOS antisense-transcript revealed that IGF-1 accelerated the degradation of iNOS mRNA, rather than the inhibition of its synthesis. Insulin-like growth factor 1 may inhibit the induction of proinflammatory cytokines and iNOS through an nuclear factor-κB-independent pathway and have a novel therapeutic potential in the prevention of liver injury.