Hepatitis B Virus-induced hFGL2 Transcription Is Dependent on c-Ets-2 and MAPK Signal Pathway
21 Nov 2008-Journal of Biological Chemistry (American Society for Biochemistry and Molecular Biology)-Vol. 283, Iss: 47, pp 32715-32729
TL;DR: C-Ets-2 protein was highly expressed in peripheral blood mononuclear cells from patients with severe chronic hepatitis B (CHB) in contrast to patients with mild CHB, and increased phosphorylation of ERK and JNK was detected in peripheralBlood mononnuclear cells from Patients with severe CHB.
About: This article is published in Journal of Biological Chemistry.The article was published on 2008-11-21 and is currently open access. It has received 47 citations till now. The article focuses on the topics: HBx & Transcription factor.
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TL;DR: This review summarizes current concepts of immune‐mediated liver injury from both clinical studies and animal models and highlights immune responses of ALF from the liver injury perspective, which combines a variety of molecular and cellular mechanisms, particularly, the contribution of cytokines and the innate immune system.
Abstract: Acute liver failure (ALF) is a syndrome of diverse aetiology, including hepatic encephalopathy, renal, cardiac and pulmonary failures, which result in a rapid loss of hepatic function. The mechanisms of liver injury contributing to ALF can be summarized into two categories: direct damage and immune-mediated liver injury. This review summarizes current concepts of immune-mediated liver injury from both clinical studies and animal models. We highlight immune responses of ALF from the liver injury perspective, which combines a variety of molecular and cellular mechanisms, particularly, the contribution of cytokines and the innate immune system. Hepatic and circulating inflammatory cytokines play a significant role in the pathophysiology of ALF including hepatocyte necrosis, extrahepatic complications and hepatocyte regeneration. Overproduction of cytokines, if unchecked, is hazardous to the host and may cause severe outcomes. Measuring pro-inflammatory cytokines in ALF may be of value for predictors of outcome. Innate and adaptive immune systems both involved in ALF contribute to immune-mediated liver injury. The innate immune response is activated much more rapidly compared with adaptive immunity, particularly in acute liver injury where the host has little time to trigger an effective adaptive immune response. From this point of view, the innate immune system may make a more profound contribution than the adaptive immune system. Furthermore, immune responses crosstalk with other physiological or pathophysiological factors, for example, coagulation factors which in turn determine the outcome of ALF and these are discussed.
213 citations
Cites background from "Hepatitis B Virus-induced hFGL2 Tra..."
...Hepatitis B virus induced hfgl2 transcription is dependent on the c-Ets-2 and MAPK signalling pathways (103)....
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TL;DR: NK cells play a pivotal role in the pathogenesis of FHF and HBV-ACLF, in which process Fas/FasL and NKG2D/NKG 2D ligand pathway contribute to the liver NK cell-mediated hepatocyte injury.
Abstract: 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-gamma and TNF-alpha 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.
124 citations
TL;DR: The frequency and cytokines secretion of circulating Th17 cells in HBV infected patients with different statuses are analyzed, and the potential association of Th17 frequency with the levels of liver injury is evaluated.
Abstract: Background and Aims: Th17 cells have been shown to mediate host defensive mechanisms in various infections, but their role in HBV infection in humans has not been well characterized In this study, we analyzed the frequency and cytokines secretion of circulating Th17 cells in HBV infected patients with different statuses, and also evaluated the potential association of Th17 frequency with the levels of liver injury
Methods: The study population consisted of 133 subjects, including 40 mild chronic hepatitis B (CHB) patients, 37 severe CHB patients, 20 acute hepatitis B (AHB) patients and 36 healthy controls The frequency of circulating Th17 cells were carried out by intracellular cytokine staining analysis and serum IL-10 levels were measured by ELISA
Results: Our data shown that AHB and severe CHB patients had a significant increase of Th17 cells frequency in peripheral blood compared with mild CHB patients and healthy control (both P < 005) The elevated prevalence of Th17 cells is positively associated with the increased serum ALT levels in severe CHB patients (r= 0457, P= 0004) but had no correlation with serum HBV DNA load In addition, the serum IL-10 were negatively correlated with the frequency of Th17 cells in PBMC from patients with chronic HBV infection (r=−0452, P < 001)
Conclusion: Th17 cells may contribute to the disease progression and pathogenesis of liver injury in HBV infected patients, and the induction of IL-10 may be one mechanism of constraining pro-inflammatory Th17 responses
84 citations
TL;DR: The global transcriptional profile of host genes in the silkworm cell line during the early phase of Bombyx mori nucleopolyhedrovirus (BmNPV) infection was analyzed and it was confirmed that the expression of 13 genes significantly increased and 7 genes significantly decreased after Bm NPV infection.
65 citations
Cites background from "Hepatitis B Virus-induced hFGL2 Tra..."
..., 1990), and Ets family proteins are reported to regulate virus-responsive genes (Han et al., 2008)....
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...In support of these speculations, mammalian Ets family proteins Ets1, Ets2 and Erl1 are known to directly activate the Human T-cell leukemia virus type 1 long terminal repeat (Bosselut et al., 1990), and Ets family proteins are reported to regulate virus-responsive genes (Han et al., 2008)....
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TL;DR: It is demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process.
Abstract: Autophagy is closely associated with the regulation of hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway. In contrast, the class III PI3K(VPS34)/beclin-1 pathway was revealed to be critical for HBx-induced autophagosome formation. Further study showed that HBx did not affect the level of VPS34 and beclin-1 expression but inhibited beclin-1/Bcl-2 association, and c-Jun NH2-terminal kinase (JNK) signaling was found to be important for this process. Moreover, it was found that HBx treatment led to the generation of reactive oxygen species (ROS), and inhibition of ROS activity abrogated both JNK activation and autophagosome formation. Of importance, ROS-JNK signaling was also revealed to play an important role in HBV-induced autophagosome formation and subsequent HBV replication. These data may provide deeper insight into the mechanisms of autophagy induction by HBx and help in the design of new therapeutic strategies against HBV infection.IMPORTANCE HBx plays a key role in diverse HBV-associated biological processes, including autophagy induction. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we found that HBx induced autophagy independently of the class I PI3K/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process. Further data showed that ROS-JNK activation by HBx resulted in the release of beclin-1 from its association with Bcl-2 to form a complex with VPS34, thus enhancing autophagosome formation. Of importance, ROS-JNK signaling was also demonstrated to be critical for HBV replication via regulation of autophagy induction. These data help to elucidate the molecular mechanisms of autophagy induction by HBx/HBV and might be useful for designing novel therapeutic approaches to HBV infection.
62 citations
Cites background from "Hepatitis B Virus-induced hFGL2 Tra..."
...induction (21), while HBx, as a multifunctional protein, is well known for its role in the regulation of diverse signaling pathways (41, 42)....
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References
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TL;DR: It is demonstrated that beta-catenin binds to the HMG-type transcription factor lymphoid enhancer factor-1 (LEF-1), resulting in a nuclear translocation of beta-Catenin both in cultured mouse cells and after ectopic expression of LEF- 1 in two-cell mouse embryos.
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Abstract: Lymphoid-specific cDNA clones were isolated that encode a nuclear protein with homology to the chromosomal nonhistone protein HMG-1 and to putative regulators of cell specialization, including the mammalian testis-determining factor SRY and fungal mating-type proteins The gene represented by the isolated cDNA clones, termed LEF-1 (lymphoid enhancer-binding factor 1), is developmentally regulated and expressed in pre-B and T lymphocytes but not in later-stage B cells or nonlymphoid tissues Both endogenous and recombinant LEF-1 were shown to bind to a functionally important site in the T-cell antigen receptor (TCR) alpha enhancer Maximal TCR alpha enhancer activity was found to parallel the cell type-specific expression pattern of LEF-1 Moreover, forced expression of recombinant LEF-1 in late stage B cells increases TCR alpha enhancer function Taken together, these data suggest that LEF-1 is a regulatory participant in lymphocyte gene expression and differentiation
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Abstract: The hepatitis B virus (HBV) X gene product trans-activates viral and cellular genes. The X protein (pX) does not bind independently to nucleic acids. The data presented here demonstrate that pX entered into a protein-protein complex with the cellular transcriptional factors CREB and ATF-2 and altered their DNA binding specificities. Although CREB and ATF-2 alone did not bind to the HBV enhancer element, a pX-CREB or pX-ATF-2 complex did bind to the HBV enhancer. Thus, the ability of pX to interact with cellular factors broadened the DNA binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This strategy of altered binding specificity may modify the repertoire of genes that can be regulated by transcriptional factors during viral infection.
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