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.
Highlights
The pathogenesis of virus-induced acute hepatic failure (AHF) is a complicated process
Our previous studies demonstrated that the fibrinogen-like protein-2 prothrombinase expressed by activated macrophages (Kupper cells) plays a crucial role in the pathogenesis of AHF induced by murine hepatitis virus strain 3 (MHV-3) or HBV (Han et al, 2008; Marsden et al, 2003; Ning et al, 1998; Zhu et al, 2005)
These results show that the chemokine receptor CXC chemokine receptor 3 (CXCR3) and its ligands (CXCL9 and CXCL10) play an important role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure
Summary
The pathogenesis of virus-induced acute hepatic failure (AHF) is a complicated process. Our previous studies demonstrated that the fibrinogen-like protein-2 (fgl2) prothrombinase expressed by activated macrophages (Kupper cells) plays a crucial role in the pathogenesis of AHF induced by murine hepatitis virus strain 3 (MHV-3) or HBV (Han et al, 2008; Marsden et al, 2003; Ning et al, 1998; Zhu et al, 2005). Subsequent transwell migration assay demonstrated that infected hepatocytes could attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in the recruitment of splenic lymphocytes. These results show that the chemokine receptor CXCR3 and its ligands (CXCL9 and CXCL10) play an important role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure
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