Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-[alpha] via Inhibition of Degradation of an Inhibitor of Nuclear Factor-[kappa]B

Background/Aims: Thalidomide inhibited tumor necrosis factor-alpha (TNF-alpha) effectively in many trials. The aim of this study was to investigate the effect of thalidomide on the expression of nuclear factor-[kappa]B (NF-[kappa]B), inhibitor of NF-[kappa]B (I[kappa]B) and TNF-alpha in a rat model of liver cirrhosis. Methods: Liver cirrhosis was achieved by intraperitoneal injection of carbon tetrachloride thrice weekly, and thalidomide (10 or 100 mg/kg/day) was given daily by intragastric route for 8 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), prealbumin (PA), hyaluronic acid (HA) and laminin (LN), and hydroxyproline (HYP), NF-[kappa]Bp65, a-smooth muscle actin (a-SMA) protein and TNF-alpha mRNA were studied in the liver, I[kappa]Balpha and TNF-alpha protein in the cytoplasm and NF-[kappa]Bp65 protein in the nucleus. Results: Compared with nontreated cirrhotic rats, the histopathology of rats given thalidomide (100 mg/kg) was significantly better. Serum ALT, AST, HA and LN and HYP content in the liver were significantly decreased and PA was elevated (p < 0.01) in this group; the expression of TNF-alpha mRNA and protein, NF-[kappa]Bp65 and a-SMA were significantly decreased and I[kappa]Balpha protein was also elevated (p < 0.01). Conclusion: Thalidomide downregulates NF-[kappa]B-induced TNF-alpha and activates hepatic stellate cells (HSC) via inhibition of I[kappa]B degradation to prevent liver cirrhosis. [PUBLICATION ABSTRACT]