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.
Kato
N
N
Department of Gastroenterology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. kato-2im@h.u-tokyo.ac.jp
Yoshida
H
H
Ono-Nita
S K
SK
Kato
J
J
Goto
T
T
Otsuka
M
M
Lan
K
K
Matsushima
K
K
Shiratori
Y
Y
Omata
M
M
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