Pathobiology : journal of immunopathology, molecular and cellular biology · 2006
Thalidomide in rat liver cirrhosis: blockade of tumor necrosis factor-alpha via inhibition of degradation of an inhibitor of nuclear factor-kappaB.
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Paul Shelley Chireyath, Lv Peng, Xiao Yan-Jv, An Ping, Liu Shi-Quan, Luo He-Sheng
Аннотация
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-kappaB (NF-kappaB), inhibitor of NF-kappaB (IkappaB) 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-kappaBp65, alpha-smooth muscle actin (alpha-SMA) protein and TNF-alpha mRNA were studied in the liver, IkappaBalpha and TNF-alpha protein in the cytoplasm and NF-kappaBp65 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-kappaBp65 and alpha-SMA were significantly decreased and IkappaBalpha protein was also elevated (p < 0.01).
CONCLUSION: Thalidomide downregulates NF-kappaB-induced TNF-alpha and activates hepatic stellate cells (HSC) via inhibition of IkappaB degradation to prevent 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-kappaBp65, alpha-smooth muscle actin (alpha-SMA) protein and TNF-alpha mRNA were studied in the liver, IkappaBalpha and TNF-alpha protein in the cytoplasm and NF-kappaBp65 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-kappaBp65 and alpha-SMA were significantly decreased and IkappaBalpha protein was also elevated (p < 0.01).
CONCLUSION: Thalidomide downregulates NF-kappaB-induced TNF-alpha and activates hepatic stellate cells (HSC) via inhibition of IkappaB degradation to prevent liver cirrhosis.
Предметные рубрики MeSH
ActinsAlanine TransaminaseAnimalsAspartate AminotransferasesCarbon TetrachlorideDown-RegulationGene Expression RegulationHydroxyprolineI-kappa B ProteinsImmunosuppressive AgentsLiverLiver Cirrhosis, ExperimentalMaleNF-KappaB Inhibitor alphaNF-kappa BRNA, MessengerRatsRats, WistarThalidomideTumor Necrosis Factor-alpha