Alteration of intrahepatic cytokine expression and AP-1 activation in transgenic mice expressing hepatitis C virus core protein.
Hepatitis C virus (HCV) infection often leads to the development of hepatocellular carcinoma (HCC), but its molecular mechanism has not been clearly elucidated. Previously, transgenic mice constitutively expressing HCV core protein have been shown to develop HCC, suggesting a pivotal role of the core protein in hepatocarcinogenesis. Here, we analyzed the expression of cytokines associated with a variety of cellular processes, including cell proliferation, in the mouse model for HCV-associated HCC to define the molecular events prior to oncogenesis. The expression of tumor necrosis factor-alpha and interleukin-1beta was increased at both protein and mRNA levels. In addition, the activities of c-Jun N-terminal kinase and activator protein-1 (AP-1), downstream effectors, were enhanced, while IkappaB kinase or nuclear factor-kappaB activities were not enhanced. Thus, the altered in vivo expression of cytokines with AP-1 activation in consequence to the core protein expression may contribute to hepatocarcinogenesis in persistent HCV infection.
Tsutsumi
Takeya
T
Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan. tmiyam@nih.go.jp
Suzuki
Tetsuro
T
Moriya
Kyoji
K
Yotsuyanagi
Hiroshi
H
Shintani
Yoshizumi
Y
Fujie
Hajime
H
Matsuura
Yoshiharu
Y
Kimura
Satoshi
S
Koike
Kazuhiko
K
Miyamura
Tatsuo
T
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D016174:Hepacivirus / Q000502:physiology*; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014758:Viral Core Proteins / Q000502:physiology*
D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases