Regulation of Fas-mediated apoptosis by NF-kappaB activity in human hepatocyte derived cell lines.
Nuclear Factor-kappaB (NF-kappaB) is known to be one of the key regulators of genes involved in survival signaling. The purpose of this study is to investigate the role of NF-kappaB activity in signaling events related to cell survival in hepatocytes, which has been supposed to be one of the most sensitive organs against Fas-induced cytotoxicity. The functions of NF-kappaB activity on Fas-mediated apoptosis in different human cell lines were investigated by a magnetic concentration system for cells with exogenous protein production. We demonstrated that the activation of NF-kappaB was triggered by anti-Fas treatment in hepatocyte derived cell lines, HepG2 and Huh-7 cells. Overexpression of kinase-inactive NF-kappaB-inducing kinase (NIK) and IkappaB kinase (IKK) inhibited the activation of NF-kappaB introduced by anti-Fas treatment in these cells. Notably, inactivation of NF-kappaB by the production of IkappaB-alpha protein made these cells more susceptible to apoptosis induced by Fas stimulation. In contrast, transient expression of NIK showed a suppressive effect on Fas-mediated apoptosis in the same cell lines. These findings suggest the involvement of NF-kappaB in suppression of Fas-mediated apoptosis in human hepatocyte derived cell lines, in which concomitant activation of this transcriptional factor was observed through the stimulation of Fas signaling.
Marusawa
H
H
Department of Medicine, Postgraduate School of Medicine, Kyoto University, Kyoto, Japan.
Hijikata
M
M
Watashi
K
K
Chiba
T
T
Shimotohno
K
K
D017209:Apoptosis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D019014:fas Receptor; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human