Activation of nuclear factor kappaB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis.
The hepatitis C virus (HCV) core protein is a multifunctional protein. It may bind to the death domain of tumor necrosis factor receptor 1 (TNFR1) and to the cytoplasmic tail of lymphotoxin-beta receptor, implying that it may be involved in the apoptosis and anti-apoptosis signaling pathways. In vitro studies have been inconclusive regarding its ability to inhibit or enhance TNF-alpha-induced apoptosis. To address this issue, electrophoretic mobility shift assay (EMSA) and immunohistochemical studies were used to show the activation of nuclear factor kappaB (NF-kappaB) in HCV-infected liver tissues and in HCV core-transfected cells. The activation of NF-kappaB was correlated with the apoptosis assays. The results showed that NF-kappaB activation could be shown in HCV-infected livers and HCV core-transfected cells. The data of EMSA correlated with those of immunohistochemical studies, which revealed a higher frequency of NF-kappaB nuclear staining in HCV-infected than in normal livers. NF-kappaB activation conferred resistance to TNF-alpha-induced apoptosis in HCV core-transfected cells. Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate sensitized them to TNF-alpha-induced apoptosis. These findings suggest that HCV infection may cause anti-apoptosis by activation of NF-kappaB and implicate a mechanism by which HCV may evade the host's immune surveillance leading to viral persistence and possibly to hepatocarcinogenesis.
Tai
D I
DI
Graduate Institute of Clinical Medicine, Chang Gung University College of Medicine, Taipei, Taiwan.
Tsai
S L
SL
Chen
Y M
YM
Chuang
Y L
YL
Peng
C Y
CY
Sheen
I S
IS
Yeh
C T
CT
Chang
K S
KS
Huang
S N
SN
Kuo
G C
GC
Liaw
Y F
YF
D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000209:etiology*; D002460:Cell Line; D005260:Female; D006526:Hepatitis C / Q000150:complications / Q000378:metabolism*; D018937:Hepatitis C Antibodies / Q000097:blood; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000097:blood / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D012367:RNA, Viral / Q000032:analysis; D013859:Thiocarbamates / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins / Q000235:genetics
D000975:Antioxidants; D018937:Hepatitis C Antibodies; D016328:NF-kappa B; D011759:Pyrrolidines; D012367:RNA, Viral; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C020972:pyrrolidine dithiocarbamic acid