Thalidomide in rat liver cirrhosis: blockade of tumor necrosis factor-alpha via inhibition of degradation of an inhibitor of nuclear factor-kappaB.
OBJECTIVE
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).


CONCLUSIONS
Thalidomide downregulates NF-kappaB-induced TNF-alpha and activates hepatic stellate cells (HSC) via inhibition of IkappaB degradation to prevent liver cirrhosis.
Paul
Shelley Chireyath
SC
Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, China.
Lv
Peng
P
Xiao
Yan-Jv
YJ
An
Ping
P
Liu
Shi-Quan
SQ
Luo
He-Sheng
HS
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013792:Thalidomide / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000199:Actins; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D002251:Carbon Tetrachloride; D006909:Hydroxyproline; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D012333:RNA, Messenger; D013792:Thalidomide; D014409:Tumor Necrosis Factor-alpha; C000606206:Nfkbia protein, rat; C498862:Acta2 protein, rat