Fulminant viral hepatitis: molecular and cellular basis, and clinical implications

Liu, Mingfeng; Chan, Chun Man; McGilvray, Ian; Ning, Qin; Levy, Gary

doi:10.1017/s1462399401002812

Cited by 47 publications

(38 citation statements)

References 90 publications

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“…MHV-3, a positive-strand RNA virus of the Coronaviridae family, produces a strain-dependent spectrum of liver diseases and immune responses [Ding et al, 1997;Ning et al, 1998Ning et al, , 1999Liu et al, 2001]. STAT1 a is reported to be essential to IFN-g and IFN-a regulated gene expression, while STAT1 b, an alternate spliceform, mediates only IFN-a-dependent gene expression.…”

Section: Introductionmentioning

confidence: 99%

STAT1 and STAT3 α/β splice form activation predicts host responses in mouse hepatitis virus type 3 infection

Ning

Berger

Luo

et al. 2003

Journal of Medical Virology

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Signal transducer and activator of transcription 1alpha (STAT1 alpha) is reported to be essential for IFN-gamma and IFN-alpha regulated gene expression, while STAT1 beta, an alternate splice-form, mediates only IFN-alpha-dependent gene expression. STAT3 alpha and STAT3 beta splice forms are also differentially activated in response to cytokines including IL-6 and IL-10. The aim of this study was to investigate whether the STAT activation will predict the host immune response to viral infection and possibly a therapeutic target for the treatment of viral infection. Mouse hepatitis virus type 3 (MHV-3) resistant strain (A/J) and sensitive mouse strains (BalB/cJ) were infected intraperitoneally (i.p.) with 100 plaque form units (pfu) of MHV-3. The mice were sacrificed at the indicated times, and livers and spleens were immediately frozen in liquid nitrogen. Nuclear extracts proteins were detected by immunoblotting. STAT1 and STAT3 activation in spleen increased 24 to 72 hr following MHV-3 infections in both sensitive and resistant mouse strains. However, over this time period, the ratio of activated alpha to beta splice-form for STAT1 and STAT3 increased above 1.0 in resistant A/J mice, while the ratio fell to <0.3 in MHV-3 sensitive Balb/cJ and C3H/HeJ strains. Activated STAT1 alpha/beta and STAT3 alpha/beta ratio in liver were similar in resistant and sensitive mouse strains. Treatment of sensitive Balb/cJ mice with neutralizing anti-TGF-beta antibody could increase the STAT1 alpha/beta ratio to <1.0 in spleens, predicting enhanced rates of survival. These results suggested that ratio of activated STAT1 alpha/beta and STAT3 alpha/beta in mixed leukocytes from spleen predict the outcome to MHV-3 infection, and may be an important marker and therapeutic target for modification of host immune response to virus infection.

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Section: Introductionmentioning

confidence: 99%

STAT1 and STAT3 α/β splice form activation predicts host responses in mouse hepatitis virus type 3 infection

Ning

Berger

Luo

et al. 2003

Journal of Medical Virology

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“…HBV infection is the leading cause of severe viral hepatitis in developing countries (1)(2)(3)(4)(5). The host immune response to virus plays a critical role in the pathogenesis of HBV infection (16,17), whereas the HBV Ag-specific CTL is an critical determinant of viral clearance (18,19) and hepatocyte damage in FHF (2, 6).…”

Section: Discussionmentioning

confidence: 99%

“…Fulminant hepatic failure (FHF) and ACLF because of hepatitis B virus (HBV) infection are the most common severe diseases requiring immediate hospitalization in China and many other Asian countries (1)(2)(3)(4)(5). The immunological mechanisms of virus-induced hepatic failure are still not fully defined.…”

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confidence: 99%

“…The immunological mechanisms of virus-induced hepatic failure are still not fully defined. The role of immune cells, especially HBV-Ag-specific CTL, is crucial in understanding HBV-related ACLF (HBV-ACLF) (2,6,7), whereas the roles of innate immune cells, especially NK cells, remain obscure. NK cells are the first cellular responders after viral infection and they provide a first line of defense against viral infection (8).…”

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Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Zou¹,

Chen²,

Han³

et al. 2009

The Journal of Immunology

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118

113

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The role of liver NK cells in virus-induced severe viral hepatitis and, subsequently, hepatic failure is not well defined. In this study, we investigated the role of liver NK cells in the development of hepatocyte necrosis in fulminant hepatic failure (FHF)and acute-on-chronic liver failure (ACLF) because of viral infection. A mouse model of FHF induced by murine hepatitis virus strain 3 (MHV-3) was used to study the role of liver NK cells. Samples from patients with hepatitis B virus-related ACLF (HBV-ACLF) were examined. After MHV-3 infection, the number of NK cells in livers of BALB/cJ mice increased markedly, peaked at 48 h postinfection, and remained at a high level until sacrifice. In peripheral blood, spleen, and bone marrow, this number decreased significantly. Expression of CD69, cytotoxic activity, and intracellular IFN-γ and TNF-α production by liver NK cells at 48 h postinfection were all significantly upregulated. Depletion of NK cells 24 h post-MHV-3 infection increased the mice survival from 0 of 18 (0%) to 4 of 18 (22.2%). Highly activated liver NK cells were cytotoxic to MHV-3-infected hepatocytes and this effect was markedly inhibited by anti-Fas ligand (FasL) plus anti-NKG2D mAbs. Furthermore, the accumulation of hepatic NK cells and increased expression of FasL and natural cytotoxicity receptors (NKp30 and NKp46) on the peripheral NK cells from patients with HBV-ACLF were correlated with disease progression. These results indicate NK cells play a pivotal role in the pathogenesis of FHF and HBV-ACLF, in which process Fas/FasL and NKG2D/NKG2D ligand pathway contribute to the liver NK cell-mediated hepatocyte injury.

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“…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). However, the infiltration of hepatic inflammatory cells should also be noted as another important pathological feature of this disease (Liu et al, 2001). Substantial accumulated inflammatory cells can not only secrete large amount of inflammatory mediators, causing deterioration of the liver microenvironment, but can also directly induce hepatocyte apoptosis and necrosis.…”

Section: Introductionmentioning

confidence: 99%

Chemokine receptor 3 (CXCR3) and its ligands contribution to virus-induced acute hepatic failure

Zou¹,

Bao²,

Zhong³

2013

Sci. Res. Essays

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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.

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Fulminant viral hepatitis: molecular and cellular basis, and clinical implications

Abstract: Fulminant viral hepatitis: molecular and cellular basis, and clinical implications 2 expert reviews in molecular medicine Accession information: (01)00281-2a.pdf (short code: txt001glt);

Cited by 47 publications

References 90 publications

STAT1 and STAT3 α/β splice form activation predicts host responses in mouse hepatitis virus type 3 infection

STAT1 and STAT3 α/β splice form activation predicts host responses in mouse hepatitis virus type 3 infection

Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Chemokine receptor 3 (CXCR3) and its ligands contribution to virus-induced acute hepatic failure

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