Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We cloned and characterized the woodchuck tumor necrosis factor (TNF) and lymphotoxin-alpha, -beta (LT-alpha, -beta) cDNAs, genes and proteins to facilitate study of the functions of these cytokines during the course of woodchuck hepatitis virus (WHV) infection. Woodchuck cDNA and genomic DNA libraries were screened with woodchuck-specific DNA probes to isolate the cDNA and gene clones for TNF, LT-alpha and LT-beta. The cDNAs for woodchuck TNF, LT-alpha and LT-beta code for proteins of 233, 205 and 310 amino acids respectively. The polypeptide encoded by each gene among woodchucks, humans and mice can differ: the human TNF, LT-alpha and LT-beta genes encode polypeptides of 233, 205 and 244 amino acids respectively, whereas the mouse TNF, LT-alpha and LT-beta genes encode polypeptides of 235, 202 and 306 amino acids respectively. In the woodchuck, there are four exons for TNF, four exons for LT-alpha and three exons for LT-beta. The RNA splicing patterns for TNF, LT-alpha and LT-beta genes are identical among woodchucks, humans and mice, except that the human LT-beta gene contains four exons. The woodchuck TNF gene promoter contains consensus sequences for binding of AP-1, AP-2, C/EBPbeta, CRE, Egr-1, Ets, NF-AT, NF-kappaB and SP-1 transcription factors. LT-alpha has AP-2, Ets, NF-kappaB, SP-1 and STAT binding sites, and LT-beta has Egr-1/SP-1, Ets and NF-kappaB binding sites. The bacterially expressed woodchuck TNF and LT-alpha proteins exhibited cytotoxic activities on both mouse L929B and woodchuck A2 cells in the presence of actinomycin D. The specific activities of TNF and LT-alpha were 2.62x10(8) units/mg and 2.22x10(3) units/mg respectively for L929B cells, and 1.05x10(9) units/mg and 3.56x10(4) units/mg respectively for A2 cells. However, only woodchuck TNF showed cytotoxic activity on human HepG2 cells, with a specific activity of 6.55x10(7) units/mg in the presence of actinomycin D. The data obtained from this study will be useful to future investigations of the TNF and LT antitumor and anti-viral activities, and their therapeutic potential in the woodchuck model for human hepatitis B virus (HBV).
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PMID:Woodchuck lymphotoxin-alpha, -beta and tumor necrosis factor genes: structure, characterization and biological activity. 1072 23

Suppressor of cytokine signaling-1 (SOCS-1), also known as STAT-induced STAT inhibitor-1 (SSI-1), is a negative feedback molecule for cytokine signaling, and its in vivo deletion induces fulminant hepatitis. However, elimination of the STAT1 or STAT6 gene or deletion of NKT cells substantially prevented severe hepatitis in SOCS-1-deficient mice, while administration of IFN-gamma and IL-4 accelerated its development. SOCS-1 deficiency not only sustained IFN-gamma/IL-4 signaling but also eliminated the cross-inhibitory action of IFN-gamma on IL-4 signaling. These results suggest that SOCS-1 deficiency-induced persistent activation of STAT1 and STAT6, which would be inhibited by SOCS-1 under normal conditions, may induce abnormal activation of NKT cells, thus leading to lethal pathological changes in SOCS-1-deficient mice.
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PMID:SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-gamma and IL-4 signaling in vivo. 1137 56

Of all the hepatitis viruses, only the hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. In this review, we discuss how these two biologically diverse viruses use common pathways to induce oxidative stress and activation of key transcription factors, known to be involved in inflammatory processes in cells. Activation of NF-kB and STAT-3 most likely contribute to the progression of viral infections to chronic hepatitis and liver oncogenesis associated with HBV and HCV infections. In this review, we focus on the mechanisms of action of HBx and HCV NS5A proteins in inducing intracellular events associated with the viral infections.
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PMID:Regulatory mechanisms of viral hepatitis B and C. 1273 9

Concanavalin A (ConA) induces natural killer T (NKT) cell-mediated liver damage. Glucocerebroside (GC) is a naturally occurring glycolipid. Our aims were to determine the effect of GC in a murine model of ConA-induced hepatitis. Mice in groups A and B were treated with GC 2 h before and 2 h following administration of ConA, respectively; group C mice were treated with ConA; group D mice was treated with GC; group E mice did not receive any treatment. Liver damage was evaluated by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver histology. The immune effect of GC was determined by fluorescence-activated cell sorter analysis of intrahepatic and intrasplenic NKT lymphocytes, measurement of cytokine levels, and Western blot analysis for STAT 1, 4, 6, and NF-kappaB expression. The effect of GC on NKT cell proliferation was assessed in vitro. Serum AST and ALT levels were markedly reduced in GC-treated group A mice compared with nontreated group C animals, and histological damage was markedly attenuated in group A. The beneficial effect of GC was associated with a 20% decrease of intrahepatic NKT lymphocytes, significant lowering of serum IFN-gamma levels, and decreased STAT1 and STAT6 expression. In vitro administration of GC led to a 42% decrease of NKT cell proliferation in the presence of dendritic cells but not in their absence. Intraperitoneally administered radioactive GC was detected in the liver and bowel. Administration of GC led to amelioration of ConA hepatitis associated with an inhibitory effect on NKT lymphocytes. GC holds promise as a new immune-modulatory agent.
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PMID:Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes. 1597 88

Hepatitis C virus (HCV) infection causes acute and chronic liver disease often leading to liver cirrhosis and hepatocellular carcinoma. Numerous studies have shown that despite induction of virus specific immunity, a curative response is often not attained; this has led to the hypothesis that HCV genes modulate immunity, thereby enabling chronic infections. This study examined the effects on immune-mediated liver injury in transgenic mice expressing core protein throughout the body and bone marrow chimeras expressing core protein in either the lymphoid compartment or liver parenchyma. Presence of core protein in the liver parenchyma but not in lymphoid cells protects from autoimmune hepatitis induced by mitogen concanavalin A (ConA). Consistent with this observation, core transgenic hepatocytes are relatively resistant to death induced by anti-Fas antibody and tumor necrosis factor alpha (TNFalpha). This protective effect is associated with preferential activation of signal transducer and activation of transcription factor 3 (STAT3) versus STAT1 in livers of ConA-injected animals. In agreement with this effect of core protein on the Janus kinase (JAK)-STAT signaling pathway, transgenic mice accelerate liver regeneration after partial hepatectomy but are not protected from hepatocyte death. In conclusion, HCV core inhibits STAT1 and stimulates STAT3 activation, which protects infected hepatocytes from attack by the cell-mediated immune system and promotes their proliferation.
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PMID:HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice. 1700 10

Reg2/RegIIIbeta is the murine homologue of the human secreted HIP/PAP C-type lectin. HIP/PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy. To assess the role of Reg2, we used Reg2-/- mice in a model of fulminant hepatitis induced by Fas and in the post-hepatectomy regeneration. Within 4 hours of J0-2 treatment (0.5 microg/g), only 50% of the Reg2-/- mice were alive but with an increased sensitivity to Fas-induced oxidative stress and a decreased level of Bcl-xL. In contrast, HIP/PAP transgenic mice were resistant to Fas, with HIP/PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl-xL. In Reg2-/- mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S-phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL-6/STAT-3 activation and mito-inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild-type mice, Reg2 could mediate the TNF-alpha/IL-6 priming signaling by exerting a negative feed-back on STAT3/IL-6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas-induced oxidative stress and delayed liver regeneration with persistent TNF-alpha/IL6/STAT3 signaling. In contrast, overexpression of human HIP/PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/PAP is therefore a critical mitogenic and antiapoptotic factor for the liver.
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PMID:Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice. 1753 37

The IL-10-like cytokine IL-22 is produced by activated T cells. In this study, we analyzed the role of this cytokine system in hepatic cells. Expression studies were performed by RT-PCR and quantitative PCR. Signal transduction was analyzed by Western blot experiments and ELISA. Cell proliferation was measured by MTS and [(3)H]thymidine incorporation assays. Hepatocyte regeneration was studied in in vitro restitution assays. Binding of IL-22 to its receptor complex expressed on human hepatic cells and primary human hepatocytes resulted in the activation of MAPKs, Akt, and STAT proteins. IL-22 stimulated cell proliferation and migration, which were both significantly inhibited by the phosphatidylinositol 3-kinase inhibitor wortmannin. IL-22 increased the mRNA expression of suppressor of cytokine signaling (SOCS)-3 and the proinflammatory cytokines IL-6, IL-8, and TNF-alpha. SOCS-1/3 overexpression abrogated IL-22-induced STAT activation and decreased IL-22-mediated liver cell regeneration. Hepatic IL-22 mRNA expression was detectable in different forms of human hepatitis, and hepatic IL-22 mRNA levels were increased in murine T cell-mediated hepatitis in vivo following cytomegalovirus infection, whereas no significant differences were seen in an in vivo model of ischemia-reperfusion injury. In conclusion, IL-22 promotes liver cell regeneration by increasing hepatic cell proliferation and hepatocyte migration through the activation of Akt and STAT signaling, which is abrogated by SOCS-1/3 overexpression.
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PMID:IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro. 1720 47

Since the discovery of the hepatitis C virus (HCV) as the major cause of non-A, non-B hepatitis in 1989, the search for specific targeted antiviral therapy for HCV (STAT-C) has been underway. Recently, major advances in the understanding of HCV biology and the development of an in vitro system of HCV replication have contributed to the selection of multiple candidate drugs for the treatment of hepatitis C. In 2006, five such candidate drugs have entered phase II clinical trials in patients chronically infected with hepatitis C, including small molecule inhibitors of the HCV NS3 serine protease and NS5B RNA-dependent RNA polymerase. This review focuses on hepatitis C protease and polymerase inhibitors that have progressed to phase II clinical development, foreshadowing the era of STAT-Cs.
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PMID:Specific targeted antiviral therapy for hepatitis C. 1733 72

Interferon alpha (IFNalpha) is the first line treatment for chronic hepatitis B and C. In order to test new IFNalpha delivery systems and investigate the function of this cytokine in the woodchuck model, the best animal model of chronic hepatitis B, we produced and purified recombinant woodchuck IFNalpha and used it to produce monoclonal antibodies. wIFNalpha5 was cloned in a prokaryotic expression system, expressed as His-tagged protein and then purified. The rwIFNalpha5 protein was found to induce STAT-3 phosphorylation, to enhance 2',5'-oligoadenylate synthetase mRNA levels and to possess a potent antiviral activity. Two monoclonal antibodies were obtained through immunization of rats with rwIFNalpha5. Both recognized rwIFNalpha5 in western blot analysis and one was able to neutralize the antiviral activity of the rwIFNalpha5 and lymphoblastoid IFNalpha preparations. Finally, a capture rwIFNalpha5 ELISA was developed using both antibodies. In summary, the tools generated in this study will allow different forms of IFNalpha delivery as well as different combination therapies in woodchuck hepatitis virus infection to be tested, thus providing useful information for the design of new strategies to treat chronic hepatitis B in humans.
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PMID:Production of recombinant woodchuck IFNalpha and development of monoclonal antibodies. 1901 34

CD4+CD25+Foxp3+ Tregs suppress autoimmune responses. In addition, they limit T cell responses during chronic infection, thereby minimizing T cell-dependent immunopathology. We sought to investigate how Tregs are regulated in the livers of patients chronically infected with HCV, where they control the balance between an adequate protective immune response and suppression of immunopathology. We found that, despite accumulating and proliferating at sites of infection in the livers of patients chronically infected with HCV, Tregs were relatively less expanded than CD4+CD25+Foxp3- effector T cells. The relative lower expansion of intrahepatic Tregs coincided with their upregulation of programmed death-1 (PD-1). PD-1 expression inversely correlated with both Treg proliferation and clinical markers of immune suppression in vivo. Consistent with the possibility that PD-1 controls Tregs, blockade of the interaction between PD-1 and programmed death-1 ligand 1 (PD-L1) enhanced the in vitro expansion and function of Tregs isolated from the livers of patients chronically infected with HCV. Blockade of the interaction between PD-L1 and B7.1 also improved the proliferation of these cells. Interestingly, both PD-1 and phosphorylated STAT-5 were overexpressed in intrahepatic Tregs in a parallel fashion in steady disease conditions, and in an alternate-fluctuating fashion during the course of severe hepatitis reactivation. Notably, PD-L1 blockade upregulated STAT-5 phosphorylation in Tregs ex vivo. These data suggest that PD-L1 negatively regulates Tregs at sites of chronic inflammation by controlling STAT-5 phosphorylation.
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PMID:PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. 1930 2


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