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Volume 24 Issue 6
December 2009
    Citation: Yong ZOU, Ge SONG, Lin DING, Tao CHEN, Xiao-jing WANG, Wei-ming YAN, Xiao-jing WANG, Xiao-ping LUO, Qin NING. Involvement of CXCR3-associated Chemokines in MHV-3 Induced Fulminant Hepatic Failure .VIROLOGICA SINICA, 2009, 24(6) : 537-544.  http://dx.doi.org/10.1007/s12250-009-3071-y
    shu

    Involvement of CXCR3-associated Chemokines in MHV-3 Induced Fulminant Hepatic Failure

    cstr: 32224.14.s12250-009-3071-y
    • 1.

      Department of Infectious Disease, Institute of Infectious Disease

    • 2.

      Department of Pediatrics, Tongji hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

    • 3.

      Department of Blood Transfusion, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China

    • Corresponding author: Qin NING, qning@tjh.tjmu.edu.cn
    • Received Date: 11 May 2009
      Accepted Date: 01 September 2009
      Available online: 01 December 2009

      Fund Project: the National Science Fund of China NSFC30672380the National Science Fund of China 30571643the National Key Basic Research Program of China 2005CB522507the National Key Basic Research Program of China 2005CB522901the National Key Basic Research Program of China 2007CB512900

    • The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)- associated chemokine [monokine induced by IFN-gamma (Mig/CXCL9) and interferon-gamma-inducible protein 10 (IP-10/CXCL10)] in the recruitment of intrahepatic lymphocytes and subsequent fulminant hepatic failure induced by MHV-3. Balb/cJ mice (6-8 weeks, female) were intraperitioneally injected with 100 PFU MHV-3.The proportions and numbers of T cells and NK cells as well as the expression of CXCR3 on T cells and NK cells in the liver, spleen and blood were analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results suggest that the CXCR3- associated chemokines (CXCL9 and CXCL10) may play an important role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure in MHV-3 infection.
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      1. Bieche I, Asselah T, Laurendeau I, et al. 2005. Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection. Virology, 332: 130-144.
          doi: 10.1016/j.virol.2004.11.009

      2. Deng G, Zhou G, Zhang R, et al. 2008. Regulatory polymorphisms in the promoter of CXCL10 gene and disease Progression in male hepatitis B virus carriers. Gastroenterology, 134: 716-726.
          doi: 10.1053/j.gastro.2007.12.044

      3. Han M, Yan W, Guo W, et al. 2008. Hepatitis B virus induced HFGl2 transcription is dependent on c-Ets-2 and MAPK signal pathway. J Biol Chem, 283: 32715-32729.
          doi: 10.1074/jbc.M806769200

      4. Lasarte J J, Sarobe P, Boya P, et al. 2003. A recombinant adenovirus encoding hepatitis C virus core and E1 proteins protects mice against cytokine-induced liver damage. Hepatology, 37: 461-470.
          doi: 10.1053/jhep.2003.50073

      5. Liu M, Chan C W, McGilvray I, et al. 2001. Fulminant viral hepatitis: molecular and cellular basis, and clinical implications. Expert Rev Mol Med, 28: 1-19.

      6. Luo Y, Luo J, Lin S, et al. 2007. Clinical significance of serum interferon-inducible protein-10 and serial changes in patients with severe hepatitis B. World J Gastroenterol, 15: 2648-2651. (in Chinese)

      7. Marsden P A, Ning Q, Fung L S, et al. 2003. The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis. J Clin Invest, 112: 58-66.
          doi: 10.1172/JCI18114

      8. Ning Q, Brown D, Parodo J, et al. 1998. Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. J Immunol, 160: 3487-3493.

      9. Ran Y, Li J, Yi X, et al. 2008. Realtionship on serum level of interferon inducible protein 10 of viral hepatitis B and hepatic function norm. Clinical Focus, 11: 1543-1545. (in Chinese)

      10. Reiberger T, Aberle J H, Kundi M, et al. 2008. CXCL10 correlates with hepatitis C viral load, hepatic inflammation and fibrosis and predicts hepatitis C virus relapse or non-response in HIV-HCV coinfection. Antivir Ther, 13: 969-976.

      11. Shi L, He J, Chen Z, et al. 2003. The expression and significance of chemokine interferon-inducible protein-10 (IP-10) in chronic hepatitis B patients. Chin J Clini Hepatol, 19: 220-221. (in Chinese)

      12. Vadan R, Gheorghe L, Becheanu G, et al. 2003. Predictive factors for the severity of liver fibrosis in patients with chronic hepatitis C and moderate alcohol consumption.Rom J Gastroenterol, 12: 183-187.

      13. Zhu C L, Yan W M, Zhu F, et al. 2005. Fibrinogen-like protein 2 fibroleukin expression and its correlation with disease progression in murine hepatitis virus type 3-induced fulminant hepatitis and in patients with severe viral hepatitis. World J Gastroenterol, 11: 6936-6940.
          doi: 10.3748/wjg.v11.i44.6936

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      Involvement of CXCR3-associated Chemokines in MHV-3 Induced Fulminant Hepatic Failure

        Corresponding author: Qin NING, qning@tjh.tjmu.edu.cn
      • 1. Department of Infectious Disease, Institute of Infectious Disease
      • 2. Department of Pediatrics, Tongji hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
      • 3. Department of Blood Transfusion, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
      • Received Date: 11 May 2009
      • Accepted Date: 01 September 2009
      Fund Project:  the National Science Fund of China NSFC30672380the National Science Fund of China 30571643the National Key Basic Research Program of China 2005CB522507the National Key Basic Research Program of China 2005CB522901the National Key Basic Research Program of China 2007CB512900

      Abstract: The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)- associated chemokine [monokine induced by IFN-gamma (Mig/CXCL9) and interferon-gamma-inducible protein 10 (IP-10/CXCL10)] in the recruitment of intrahepatic lymphocytes and subsequent fulminant hepatic failure induced by MHV-3. Balb/cJ mice (6-8 weeks, female) were intraperitioneally injected with 100 PFU MHV-3.The proportions and numbers of T cells and NK cells as well as the expression of CXCR3 on T cells and NK cells in the liver, spleen and blood were analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results suggest that the CXCR3- associated chemokines (CXCL9 and CXCL10) may play an important role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure in MHV-3 infection.

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