INSULIN-LIKE GROWTH FACTOR 1 PREVENTS LIVER INJURY THROUGH THE INHIBITION OF TNF-α AND INOS INDUCTION IN D-GALACTOSAMINE AND LPS-TREATED RATS

• DOI: 10.1097/shk.0b013e31815d0780
• Publication Date: 2008-05-13T07:07:11Z
• Authors: Takeshi Hijikawa; Masaki Kaibori; Yoichiro Uchida; Masanori Yamada; Kosuke Matsui; Takashi Ozaki; Yasuo Kamiyama; Mikio Nishizawa; Tadayoshi Okumura
• Keywords: Lipopolysaccharides; Male; 0301 basic medicine; Tumor Necrosis Factor-alpha; RNA Stability; Nitric Oxide Synthase Type II; Bilirubin; Galactosamine; Rats; 3. Good health; Rats, Sprague-Dawley; 03 medical and health sciences; Liver; Enzyme Induction; Animals; Humans; RNA, Messenger; Insulin-Like Growth Factor I; Liver Failure; Transaminases

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(-1)) and LPS (16 microg kg(-1)) (GalN/LPS) to induce acute liver failure. Insulin-like growth factor 1 (3.2 mg kg(-1)) 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-alpha, IL-1 beta, 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-kappa B. 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-kappa B-independent pathway and have a novel therapeutic potential in the prevention of liver injury.