Insulin-like growth factor 1 prevents liver injury through the inhibition of TNF-alpha 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(-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.
Hijikawa
Takeshi
T
The Department of Surgery, Kansai Medical University, Moriguchi, Osaka, Japan.
Kaibori
Masaki
M
Uchida
Yoichiro
Y
Yamada
Masanori
M
Matsui
Kosuke
K
Ozaki
Takashi
T
Kamiyama
Yasuo
Y
Nishizawa
Mikio
M
Okumura
Tadayoshi
T
D000818:Animals; D001663:Bilirubin / Q000097:blood; D004790:Enzyme Induction / Q000187:drug effects; D005688:Galactosamine / Q000633:toxicity*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D005688:Galactosamine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000637:Transaminases; D001663:Bilirubin