Abstract

The role of chemokines in virus-induced acute hepatic failure is not well defined. In this study, we investigated the role of CXC chemokine receptor 3 (CXCR3) and its ligands chemokine Mig/CXCL9 (monokine induced by IFN-gamma) and IP-10/CXCL10 (interferon-gamma-inducible protein 10) in the recruitment of intrahepatic lymphocytes and subsequent acute hepatic failure. Balb/cJ mice (6 to 8 weeks, female) were intraperitoneally injected with 100 PFU murine hepatitis virus strain 3 (MHV-3). The proportions and numbers of T cells and NK cells in liver, spleen, and blood as well as the expression of CXCR3 on T cells and NK cells post MHV-3 infection was 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 and CXCL10 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 indicate that interactions involving CXCR3 and its ligands (CXCL9 and CXCL10), especially CXCL10 may play a key role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and acute hepatic failure.

Key words: Chemokine, interferon gamma-inducible protein 10 (CXCL10), hepatic failure, natural killer cell, T cell.