Activation of intracellular signaling by hepatitis B and C viruses: C-viral core is the most potent signal inducer.
To clarify the effects of hepatitis C virus (HCV) infection on hepatocytes, we analyzed and compared the induction of intracellular signals by HCV and hepatitis B virus (HBV) proteins. We examined the influence of 7 HCV (core, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) and 4 HBV (precore, core, polymerase, and X) proteins on 5 well-defined intracellular signaling pathways associated with cell proliferation, differentiation, and apoptosis by use of a reporter assay. Viral protein-expression vectors were cotransfected into mammalian cells with reporter vectors having a luciferase gene driven by the following inducible cis-enhancer elements: the cyclic adenosine monophosphate response element, the serum response element (SRE), and the binding sites for nuclear factor kappaB (NF-kappaB), activator protein 1 (AP-1), and serum response factor (SRF). In addition, the activation of signals by HCV proteins was examined in a reporter plasmid having a natural interleukin-8 (IL-8) promoter upstream of a luciferase gene. Of 11 HCV and HBV proteins, HCV core had the strongest influence on intracellular signals, especially NF-kappaB-, AP-1-, and SRE-associated pathways. HCV core's activation level exceeded that of HBV X protein, a well-characterized transactivator of these signals. Moreover, HCV core activated the IL-8 promoter through NF-kappaB and AP-1. For the other proteins, HCV NS4B showed signal activation, but signals were activated at a lesser extent. The luciferase reporter assay, a recently introduced technique, helped in the elucidation of molecular events underlying the inflammatory and proliferation process in the liver induced by HCV.
Department of Gastroenterology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. kato-2im@h.u-tokyo.ac.jp
N
N
Kato
H
H
Yoshida
S K
SK
Ono-Nita
J
J
Kato
T
T
Goto
M
M
Otsuka
K
K
Lan
K
K
Matsushima
Y
Y
Shiratori
M
M
Omata
D015153:Blotting, Western; D016174:Hepacivirus / Q000502:physiology*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins
D016209:Interleukin-8; D016328:NF-kappa B; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014758:Viral Core Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C069130:nucleocapsid protein, Hepatitis C virus