Reversal effect of thalidomide on established hepatic cirrhosis in rats via inhibition of nuclear factor-kappaB/inhibitor of nuclear factor-kappaB pathway.
BACKGROUND
Suppression of nuclear factor-kappaB (NF-kappaB)/inhibitor of nuclear factor-kappaB (IkappaB) signaling pathway is a potential property of thalidomide. This study was designed to investigate the effects of thalidomide on expressions of NF-kappaB, IkappaB and intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule (VCAM-1) in established rat liver cirrhosis.


METHODS
Rat liver cirrhosis was achieved by IP injection of carbon tetrachloride (CCl4) three times weekly for 8 weeks. CCl4 was then discontinued and thalidomide (100 mg/kg) or its vehicle was administered daily by gavage for 6 weeks. Hydroxyproline (HYP) content in liver was detected by biochemical assay. NF-kappaBp65, ICAM-1, VCAM-1 and alpha-smooth muscle actin (alpha-SMA) protein in the liver, IkappaBalpha protein in cytoplasm and NF-kappaBp65 protein in nucleus and ICAM-1, VCAM-1 mRNA levels in the liver were studied using immunohistochemistry, Western blot, and reverse transcriptase polymerase chain reaction, respectively.


RESULTS
Compared with the spontaneous recovery of cirrhosis, the histopathology of liver of rats given thalidomide was significantly improved. HYP content in liver, the expressions of ICAM-1, VCAM-1 mRNA and protein, NF-kappaBp65 and alpha-SMA protein were decreased significantly and IkappaBalpha protein in liver was elevated significantly in this group.


CONCLUSIONS
Thalidomide may exert its effect on downregulation of NF-kappaB-induced adhesion molecules and activation of hepatic stellate cell via inhibition of degradation of IkappaB to reverse established rat hepatic cirrhosis.
Lv
Peng
P
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, PR, China.
Luo
He-Sheng
HS
Zhou
Xiao-Ping
XP
Xiao
Yan-Jv
YJ
Paul
Shelley Chireyath
SC
Si
Xin-Min
XM
Zhou
Yan-Hong
YH
D000199:Actins / Q000032:analysis / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D006909:Hydroxyproline / Q000032:analysis; D020672:I-kappa B Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000032:analysis / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism
D000199:Actins; D006909:Hydroxyproline; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D012333:RNA, Messenger; D013792:Thalidomide; D051996:Transcription Factor RelA; D019010:Vascular Cell Adhesion Molecule-1; C000606206:Nfkbia protein, rat; C498862:Acta2 protein, rat