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

To elucidate the role of apoptosis in the pathological lesion of hepatitis B virus (HBV) infection, biopsied liver tissue specimens of 38 patients with chronic hepatitis B of varying severity were investigated with in situ immunohistochemistry and TUNEL test. Apoptotic hepatocytes were found to be rare, while the nuclei of many cells were positively stained with TUNEL, suggesting 3'-OH ends generated as the DNA was impaired. Of the 17 cases with mild lesion or without piecemeal necrosis, 14 were negative or weakly positive with both Fas and TUNEL test. Of the 7 cases with piecemeal and bridging necrosis, none was strongly positive. In the 14 cases with active hepatitis and early cirrhosis, strongly positive results with Fas were found in 9 and with TUNEL in 3 respectively. It is suggested that the cytotoxic T lymphocyte (CTL)-Fas-apoptosis mechanism was involved in the hepatocyte death of hepatitis B as well. The Fas expression, DNA damage and apoptotic cells distributed mostly in the piecemeal necrosis region, and the ballooning and the necrotic hepatocytes were also clustering in this region. As both the apoptosis and necrosis are mediated by CTL, they are closely related: while transducted by different ways, they occurred independently.
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PMID:[Fas expression and DNA impairment of hepatocyte in chronic hepatitis B]. 959 43

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas-expressing cells. A matrix metalloproteinase-like enzyme cleaves the membrane-bound FasL to produce the soluble FasL (sFasL). Since FasL has been reported to play a pivotal role in the development of hepatitis, we evaluated clinical significance of serum sFasL in acute liver injury including acute self-limited and fulminant hepatitis. Serum sFasL in 19 patients including 12 with acute self-limited hepatitis and 7 with fulminant hepatitis was measured by an enzyme-linked immunosorbent assay (ELISA). The clinical data consisted of 18 indices including age, sex, liver function tests, hepatocyte growth factor (HGF), outcome and sFasL. Serum sFasL in fulminant hepatitis is 0.06+/-0.01 ng/ml, being identical to that in acute self-limited hepatitis, Serum sFasL is positively correlated with AST and ALT (p<0.0001 and p<0.0001). The factors associated with outcome of the patients were HGF, albumin, prothrombin time, platelet count, cholinesterase and leukocyte count in this order. Serum sFasL serves as an indicator of liver injury in acute self-limited and fulminant hepatitis.
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PMID:Clinical significance of serum soluble Fas ligand in patients with acute self-limited and fulminant hepatitis. 975 39

Involvement of malignant lymphoma in the liver inducing fulminant hepatic failure has rarely been reported. Therefore, a close association between some lymphoma types with severe liver damage and the mechanism underlying the liver damage is intriguing. Three malignant lymphoma cases, which were clinically diagnosed as fulminant hepatitis, were collected from the autopsy records of Kawasaki Medical School (Kurashiki, Japan). All three cases were characterized by the presence of hepatosplenomegaly without superficial lymph node swelling, high elevation of transaminase and lactate dehydrogenase (LDH; especially LDH-2), and a quite aggressive clinical course. Immunohistochemically, the tumor cells in all three cases were positive for T cell intracellular antigen (TIA-1), which is a cytolytic protein in cytotoxic T and natural killer (NK) cells. The lymphomas were CD8+ peripheral T cell lymphoma (case 1), CD56+ T/NK cell lymphoma (case 2), and T cell lymphoma in a patient with mosquito hypersensitivity (case 3). Epstein-Barr virus infection was demonstrated on the tumor cells of cases 2 and 3 using an in situ hybridization method and those cases showed high titers of serum interferon-gamma and Fas. Frequent apoptosis of liver cells, where the lymphoma cells had infiltrated, was revealed by a terminal deoxyribosyl transferase-mediated deoxyuridine nick end-labeling (TUNEL) method. The findings in this study suggest that fulminant hepatic injury is closely associated with cytotoxic molecule TIA-1 expression of the lymphoma cells and that some specific mechanism may be involved in liver damage.
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PMID:Expression of cytotoxic molecule TIA-1 in malignant lymphomas mimicking fulminant hepatitis. 977 8

Concanavalin A (Con A)-induced hepatitis is an experimental hepatitis model in which hepatic injury is caused by the action of cytokines produced by T cells. Using IFN-gamma-deficient mice, we previously demonstrated that IFN-gamma plays a central role in Con A-induced hepatitis. Here, we show that development of the disease is completely suppressed in gld/gld mice, in which Fas ligand is defective. In contrast, suppression of the disease in Ipr/Ipr mice was incomplete, since a small amount of the fas mRNA was produced in these mice. The data indicate that activation of the Fas/Fas ligand system is a necessary step in the development of Con A-induced hepatitis. Furthermore, we found that not only fas but also caspase-1 expression was reduced in IFN-gamma-deficient mice. Since caspase-1 is an integral component of Fas signal transduction, these observations suggest that IFN-gamma-induced activation of both fas and caspase-1 expression causes enhancement of hepatocyte apoptosis resulting in the development of hepatitis.
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PMID:Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis. 986 46

Adenovirus vectors transduce liver hepatocytes with extreme efficiency; however, transgene expression is eliminated within 2 weeks. Extinction of transgene expression has been attributed to infiltrating cytotoxic T lymphocytes (CTLs) in the liver in a process that resembles a number of human diseases, including viral and autoimmune hepatitis. In this study we investigated the role of Fas-Fas ligand interactions in killing of vector-transduced hepatocytes in vitro and in vivo. Intrahepatic lymphocytes (IHLs) isolated from livers of mice administered adenovirus vector demonstrated cytolytic activity against vector-infected primary hepatocytes. The in vitro CTL activity of the IHLs involving both CD4+ and CD8+ T cells was MHC class I restricted and could be blocked by soluble Fas-IgG. Adoptive transfer of IHLs from immune-competent mice immunized with Ad-lacZ into Ragl-deficient mice previously infused with Ad-lacZ resulted in rapid elimination of beta-galactosidase-transduced hepatocytes. Transfer of these cells into Fas-deficient mice (B6-lpr) failed to eliminate lacZ expression; likewise IHLs from immunized FasL-deficient mice (B6-gld) failed to eliminate lacZ expression in Rag1-deficient mice. Finally, in vivo administration of soluble Fas-IgG abrogated the ability of Ad-lacZ-primed IHLs to eliminate transgene expression. These studies establish an essential role for Fas-Fas ligand interactions in the mechanism of elimination of adenoviral vector-mediated transgene expression in the liver.
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PMID:Fas-Fas ligand interactions play a major role in effector functions of cytotoxic T lymphocytes after adenovirus vector-mediated gene transfer. 1002 50

Autoreactive T lymphocytes probably cause pancreatic beta-cell death by inducing apoptosis. To visualize apoptotic beta-cells in vivo, we accelerated diabetes of NOD mice with cyclophosphamide (CY) or adoptive transfer. We also studied whether Fas-mediated apoptosis is involved in the development of diabetes by administrating anti-Fas ligand (FasL) Ab and by grafting Fas-deficient neonatal pancreas from NOD-lpr/lpr mice. Apoptotic cells were clearly shown 8 days after CY treatment. Beta-cell apoptosis was also observed after adoptive transfer but in a different kinetic pattern. Anti-FasL Ab administration failed to inhibit diabetes after CY treatment or adoptive transfer, while it inhibited Con A-induced hepatitis. Fas-deficient neonatal pancreata were destroyed by lymphocytic infiltration in diabetic NOD mice. Our results clearly demonstrate apoptosis of beta-cells in accelerated diabetes and indicate that Fas-FasL interaction is not involved in diabetes of NOD mice, contrary to the previous reports.
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PMID:Apoptosis of pancreatic beta-cells detected in accelerated diabetes of NOD mice: no role of Fas-Fas ligand interaction in autoimmune diabetes. 1006 61

Experimental hepatitis induced by tumor necrosis factor in D-(+)-galactosamine-sensitized mice or by an agonistic anti-Fas antibody in normal mice is accompanied by dramatic apoptosis of hepatocytes. Apoptosis is the final result of activation of a cascade of caspases. We used caspase-1-/- mice, generated by gene targeting, to study the role of this protease in TNF- and anti-Fas-induced lethal hepatitis. We found that mutant mice exhibited the typical caspase-1-/- phenotype, since they resisted to a lethal injection of LPS and released no interleukin-1beta in the circulation, in contrast to wild-type littermates. When caspase-1-/- mice were challenged with different doses of tumor necrosis factor/D-(+)-galactosamine or with anti-Fas, no increased survival was observed compared with control mice. Furthermore, apoptosis in the livers of these mice and serum levels of alanine aminotransferase were not reduced. These data indicate that caspase-1 deficiency does not lead to reduced apoptosis in these models, either because caspase-1 is irrelevant in this model or because of functional redundancy.
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PMID:Caspase-1 is not involved in experimental hepatitis in mouse. 1006 84

The death receptor Fas transduces apoptotic death signaling upon stimulation by Fas ligand and plays a key role in viral hepatitis. When hepatitis-B virus (HBV) infects hepatocytes, the Fas ligand/Fas system responds as the triggering machinery of hepatitis. However, some HBV-infected cells may circumvent Fas-mediated apoptosis and transform to hepatoma cells, as do PLC/PRF/5 hepatoma cells. Therefore, in the present study, we used PLC/PRF/5 hepatoma cells to investigate this ability to avoid Fas-mediated apoptosis. When the cells were treated with an agonistic Fas antibody, they showed resistance to Fas-mediated apoptosis. In contrast, HepG2 cells of the same hepatoma line succumbed. Caspase 3 and 8, which are essential regulators for Fas-mediated cell death, were expressed in both hepatoma cell lines, but only HepG2 cells showed activation of the caspases. A comparison study of expression of other death-associated factors between PLC/PRF/5 and HepG2 cells revealed no apparent differences. However, Far-Western blotting analysis using the Fas death domain (FDD) showed a significant difference. Molecular weight comparison and immunoblotting analysis revealed that PLC/PRF/5 cells lack the FDD-associated protein FADD. In addition, FDD-injected HepG2 cells showed a resistance to Fas-mediated apoptosis, and PLC/PRF/5 cells acquired Fas-sensitivity by FADD injection. Here, we propose that a functional absence of FADD is one of the pathways for the carcinogenesis of HBV-infected hepatocytes.
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PMID:Functional absence of FADD in PLC/PRF/5 hepatoma cells: possible involvement in the transformation to hepatoma in HBV-infected hepatocytes. 1032 Jun 34

The Fas receptor, also known as APO-1 or CD95, has emerged as a key initiator of apoptotic programmed cell death in a variety of cell types. CD4(+) T cells are unique in their ability to commit "suicide" by stimulating their own Fas receptors with secreted or membrane-bound Fas ligand. This takes place in the setting of repeated stimulation with T-cell antigens and is thought to be a mechanism for controlling the expansion of T cells during viral infections and autoimmune disease states. T cells can also trigger apoptosis in B cells, macrophages, and other cell types through Fas ligand. These interactions negatively regulate the immune system but can also contribute to immunopathology, as occurs in Fas-mediated damage of target tissues in hepatitis and other organ-specific autoimmune diseases. The dual role of Fas in the immune response complicates the understanding of its role in disease states and may limit its potential as a therapeutic target. Despite the many roles of Fas in immunoregulation, findings in experimental mouse strains and human patients with genetic deficiencies in the Fas pathway have shown that the main result of disrupting this pathway in vivo is systemic autoimmunity and a predisposition toward lymphoid malignancies. The role of Fas in various cell types and the lessons we have learned from Fas-deficient patients with the autoimmune lymphoproliferative syndrome will be discussed.
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PMID:The role of Fas and related death receptors in autoimmune and other disease states. 1032 2

The effect of cyclosporine A (CsA) on anti-Fas antibody-induced hepatitis was studied. The administration of anti-Fas antibody (250 microg/kg) to mice elevated plasma alanine aminotransferase (ALT) activity at 3 hr. This anti-Fas antibody-induced elevation of ALT was inhibited by treatment with CsA (10, 30 and 100 mg/kg) in a dose-dependent manner. Anti-Fas antibody administration elevated CPP32-like protease activity at 3 hr in mouse liver, and this elevation of CPP32-like activity was inhibited by treatment with CsA. The present results show that CsA treatment inhibits the anti-Fas antibody-induced apoptotic process of hepatitis, at least in part, by affecting a reaction upstream of CPP32-like protease activation.
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PMID:The protective effect of cyclosporine A on anti-Fas antibody-induced hepatitis in mice. 1036 89


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