KANAI Fumihiko University of Hospital, The University of Tokyo, Research Associate, 医学部・附属病院, 助手 (70334399)
SHIRATORI Yasushi University of Hospital, The University of Tokyo, Associate Professor, 医学部・附属病院, 講師 (70196624)
|Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
Hepatitis viruses cause persistent infection, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In this study, the influence of hepatitis B, C, and delta virus (HBV, HCV, and HDV, respectively) proteins on the function of hepatocyte, especially the induction of inflammatory cytokines, was investigated. Among 15 viral proteins, HCV core protein activated NF-_KB, AP-1, MAP kinase, and P53-associated signaling pathways. HCV core protein upregulated interleukin-16 and -8 promoters through NF-_KB activation, and increased p21 expression through p53 activation. The core protein activated NF-_KB pathway through IKKβand tumor necrosis factor receptor-associated factor (TRAF), and enhanced p53 function through augmentation of DNA-binding affinity and transcriptional ability. The core protein may directly promote cell proliferation and induce an inflammatory reaction by activating NF-_KB, AP-1, and MAP kinase-assosiated signaling pathways. On the other hand, the core protein could enha
nce p53 function. These opposing functions may result in exquisitely balancing the proliferation of hepatocytes infected with HCV.
Apoptosis is related to inflammation of the liver in chronic hepatitis. In HCV core protein-expressing cell, activation of caspase 3 was inhibited and Bcl-x_L expression was increased. The core protein enhances the Bcl-x_L expression through activating MAP kinase cascade, and thus inhibits apoptotic signal induced by Fas at the mitochondria level. Core protein-mediated Bcl-x_L induction may be one of the mechanisms underlying its inhibition of apoptosis, which might contribute to the pathogenesis of HCV.
HCV NS4A and NS4B proteins generally suppressed cellular translation process (translational shutoff). This function may be involved in HCV infection and help its survival in host cells. In addition to HCV proteins, HDV large antigen activated SRF-associated pathway and synergistically activated SRE with HBx protein.
In summary, hepatitis virus proteins may influence intracellular signaling pathways, induce inflammatory cytokines, and thus cause inflammation of the liver. Less