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)

It has been postulated that tumor cells expressing Fas ligand (FasL) can evade immune surveillance by inducing apoptosis in T cells expressing Fas. In this study, we investigated FasL expression in 13 human hepatoma cell lines. Strong FasL expression was detected by reverse transcription-polymerase chain reaction or immunofluorescence in Hep G2.2.15, in which the hepatitis-B-virus (HBV) genome was transfected, and in SNU-354, which showed HBx transcripts. To determine the biological activity of FasL, Hep G2.2. 15 was co-cultured with MOLT-4, T-cell-leukemia cells. Hep G2.2.15 induced apoptosis in MOLT-4 and this was inhibited by the antagonistic anti-Fas antibody, ZB4. For further analysis of the role of HBx in the induction of FasL, PLC/PRF/5 cells were transfected transiently with the HBV genome, or HBx, or the frameshift mutant of HBx. In PLC/PRF/5 cells transfected with the HBV genome or HBx but not in cells transfected with the frameshift mutant of HBx, FasL expression was detected. Our data suggest that HBx plays a role in the induction of FasL in hepatoma cells and in the escape from immune surveillance.
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PMID:Expression of fas ligand in human hepatoma cell lines: role of hepatitis-B virus X (HBX) in induction of Fas ligand. 1040 75

The interferon-gamma (IFN-gamma) transgenic mouse expresses the IFN-gamma gene strongly in the liver and develops chronic hepatitis from 6-10 weeks of age. Previously we reported the detection of hepatocyte apoptosis and the expression of the Fas system in the transgenic mouse liver. The objective of the present study was to examine the possible development of favorable conditions for predisposing cells to malignancy. The connection between the cell cycle and cancer has become evident, and the relation of cyclin D1 (CD1) with hepatocellular carcinomas has been strengthened. In the liver of transgenic mice of 48 weeks of age, c-myc and CD1 gene expression was induced, indicating progression of the cell cycles. p21 gene expression in the transgenic mouse liver might counteract cell-cycle progression promoted by c-myc and CD1. In the liver of 8-week-old transgenic mice, expression of c-myc mRNA was correlated with the levels of plasma transaminase activities. In these 8-week-old transgenic mice, however, CD1 mRNA was not induced, regardless of the progression of hepatitis. Based on these results, we conclude that long lasting hepatitis may lead to favorable conditions for predisposing cells to malignancy.
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PMID:Long lasting chronic hepatitis is accompanied by cyclin D1 gene expression in the mouse. 1042 76

Paraffin-embedded liver tissue from 60 biopsied or autopsied cases, including 20 cases each of acute mild hepatitis, chronic active hepatitis and active cirrhosis were studied with immunohistochemical double labelling technique by using polyclonal anti-Fas and anti-Fas ligand. The detection rates for Fas and Fas ligand were 76.7% (46/60) and 70.0% (42/60), respectively. Fas antigen was located in cytoplasm of hepatocytes. Fas ligand was expressed mainly in infiltrating lymphocytes in portal or periportal areas (34/42, 80.9%) and also in the cytoplasm of some hepatocytes (25/42, 59.5%). The distribution of Fas ligand-positive hepatocytes was similar to that of Fas-positive hepatocytes in liver tissue. The positive cells were scattered in the intralobular areas in acute mild hepatitis, but they were more commonly aggregated in periportal areas, especially near the edges of the piecemeal necrosis region or in infiltrating mononucleocytes in chronic active hepatitis and active cirrhosis, Double labelling studies showed that both Fas and Fas ligand might be expressed in the same or different hepatocytes of the same area. Our results suggest that Fas-Fas ligand system may play an important role in liver cell injury due to hepatitis B virus infection.
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PMID:[Expression of Fas and Fas ligand in liver tissue infected with hepatitis B virus]. 1043 77

Fas ligand (CD95L) and tumor necrosis factor-alpha (TNF-alpha) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-alpha-mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing BCL-XL in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous Bcl-xL or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-alpha caused massive apoptosis and death only when transcription was inhibited. Under these conditions, PK-BCL-XL mice were partially protected from liver injury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-alpha receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.
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PMID:Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice. 1048 97

The CD3+/TCRalphabeta+ T-cell-mediated hepatic inflammation induced by Propionibacterium acnes could be divided into an acute and a chronic phase. The acute phase occurred within 72 h after injection and displayed hepatic apoptosis. Anti-TNFalpha antibody inhibited both the P. acnes-induced hepatic apoptosis and lymphocyte infiltration seen in this phase, indicating the involvement of this cytokine. Thereafter, a chronic phase was manifested from days 7 to 14 after injection. It was characterized as granulomatous inflammation admixed with apoptosis of infiltrating lymphocytes and some hepatocytes. Immunohistochemical staining showed that the infiltrating lymphocytes displayed TNFalpha, TNF type I receptor and a variety of cytokines including IL-1beta, IL-4, IL-6, IL-10, IFNgamma or IL-12. Interestingly, in naive mice, the arteries in the liver constitutively expressed IFNgamma. Its expression appeared to be substantially increased at 48 h, decreased at 72 h, and increased again on day 14 after P. acnes injection. Furthermore, Fas or FasL was only detected on the lymphocytes within the granuloma. We conclude that P. acnes can induce a TNFalpha-mediated acute hepatic apoptosis which subsequently progress to a T-cell-mediated granulomatous hepatitis with increased expression of multiple cytokines and Fas/FasL.
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PMID:Propionibacterium acnes induces acute TNFalpha-mediated apoptosis of hepatocytes followed by inflammatory T-cell-mediated granulomatous hepatitis in mice. 1049 42

There is considerable interest in the role of Fas protein as it induces apoptotic cell death when ligated by its natural ligand (FasL). Interaction between Fas and FasL is a crucial mechanism for clonal deletion and immune tolerance and privilege, control of T cell expansion during immune responses and killing by cytotoxic T lymphocytes. Loss of function of the system can block lymphocyte apoptosis and cause lymphoproliferation and autoimmunity but, when the system overfunctions, it can end to tissue injury and destruction. Recent studies have demonstrated that the Fas/FasL system is implicated in the pathogenesis of several human diseases ranging from AIDS to autoimmunity and lymphoproliferation, hepatitis, multiple sclerosis and transplant rejection. It is conceivable that modulating the activity of the Fas/fasL pathway would have clinical applications for the treatment of these patients.
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PMID:Fas/Fas ligand on the road: an apoptotic pathway common to AIDS, autoimmunity, lymphoproliferation and transplantation. 1049 26

Caspase-3 is essential for Fas-mediated apoptosis in vitro. We investigated the role of caspase-3 in Fas-mediated cell death in vivo by injecting caspase-3-deficient mice with agonistic anti-Fas Ab. Wild-type controls died rapidly of fulminant hepatitis, whereas the survival of caspase-3-/- mice was increased due to a delay in hepatocyte cell death. Bcl-2 expression in the liver was dramatically decreased in wild-type mice following anti-Fas injection, but was unchanged in caspase-3-/- mice. Hepatocytes from anti-Fas-injected wild-type, but not caspase-3-/-, mice released cytochrome c into the cytoplasm. Western blotting confirmed the lack of caspase-3-mediated cleavage of Bcl-2. Presumably the presence of intact Bcl-2 in caspase-3-/- hepatocytes prevents the release of cytochrome c from the mitochondria, a required step for the mitochondrial death pathway. We also show by Western blot that Bcl-xL, caspase-9, caspase-8, and Bid are processed by caspase-3 in injected wild-type mice but that this processing does not occur in caspase-3-/- mice. This study thus provides novel in vivo evidence that caspase-3, conventionally known for its downstream effector function in apoptosis, also modifies Bcl-2 and other upstream proteins involved in the regulation of Fas-mediated apoptosis.
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PMID:In vivo evidence that caspase-3 is required for Fas-mediated apoptosis of hepatocytes. 1052 93

The Fas ligand (FasL)/Fas and the perforin-granzyme cytotoxic pathways presumably play a central role in the development of hepatocellular injury in viral hepatitis. To recognize the potential contribution of FasL and perforin-based cell killing in hepadnaviral infection, we adopted a cytotoxic assay using murine Fas+ P815 and human Fas- K562 cells as targets. Freshly isolated peripheral blood mononuclear cells (PBMC) from woodchucks with newly acquired woodchuck hepatitis virus (WHV) infection (n = 6), with chronic WHV hepatitis (n = 9), and from healthy animals (n = 11) were used as effector cells. We have found that woodchuck lymphoid cells kill cell targets via both the FasL/Fas and the perforin death pathways. The contribution of Fas-dependent cytolysis was ascertained in blocking experiments with anti-Fas antibody and by incubation of PBMC with cyclohexamide to prevent de novo synthesis of FasL. The involvement of the perforin pathway was confirmed by treatment of K562 cells with colchicine to inhibit the microtubule-dependent perforin release. Comparative analysis showed that peripheral lymphoid cells from acute WHV hepatitis, but not those from chronic WHV infection, are more cytotoxic and that this increase seems to be entirely due to activation of perforin-mediated killing. The data indicate that acute infection in woodchucks is associated with the augmented capacity of lymphoid cells to elicit perforin-dependent killing, but in chronic infection, independent of the severity of liver disease and duration of chronicity, these cells have the same or lower cytotoxic potential as PBMC from healthy controls. These findings suggest a role for non-specific cellular immunity, presumably natural killer (NK) cells, in the control of early WHV infection and in the progression of chronic hepatitis.
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PMID:Perforin and Fas/Fas ligand-mediated cytotoxicity in acute and chronic woodchuck viral hepatitis. 1054 Jan 61

Lethal hepatitis can be induced by an agonistic anti-Fas Ab in normal mice or by TNF in mice sensitized to d -(+)-galactosamine or actinomycin D. In all three models, we found that apoptosis of hepatocytes is an early and necessary step to cause lethality. In the three models, we observed activation of the major executioner caspases-3 and -7. Two acute-phase proteins, alpha1-acid glycoprotein and alpha1-antitrypsin, differentially prevent lethality: alpha1-acid glycoprotein protects in both TNF models and not in the anti-Fas model, while alpha1-antitrypsin confers protection in the TNF/d -(+)-galactosamine model only. The protection is inversely correlated with activation of caspase-3 and caspase-7. The data suggest that activation of caspase-3 and -7 is essential in the in vivo induction of apoptosis leading to lethal hepatitis and that acute phase proteins are powerful inhibitors of apoptosis and caspase activation. Furthermore, Bcl-2 transgenic mice, expressing Bcl-2 specifically in hepatocytes, are protected against a lethal challenge with anti-Fas or with TNF/d -(+)-galactosamine, but not against TNF/actinomycin D. The acute-phase proteins might constitute an inducible anti-apoptotic protective system, which in pathology or disturbed homeostasis prevents excessive apoptosis.
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PMID:Activation of caspases in lethal experimental hepatitis and prevention by acute phase proteins. 1055 44

The effect of pentoxifylline on anti-Fas antibody-induced hepatitis was studied. The administration of anti-Fas antibodies (250 microg/kg, i.v.) to mice elevated plasma alanine aminotransferase (ALT) activity at 3 h. This anti-Fas antibody-induced elevation of ALT was inhibited by treatment with pentoxifylline at the doses of 10 and 100 mg/kg (i.p.). Anti-Fas antibody administration also elevated the CPP32-like protease activity in the liver at 3 h. Although pentoxifylline at 100 mg/kg, i.p., inhibited the anti-Fas antibody-induced elevation of plasma ALT, this treatment did not significantly inhibit the anti-Fas antibody-induced elevation of CPP32-like activity. The present results clearly showed that treatment with pentoxifylline inhibited anti-Fas antibody-induced hepatitis, at least in part, by affecting a reaction downstream of CPP32-like protease activation.
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PMID:Pentoxifylline inhibits anti-Fas antibody-induced hepatitis by affecting downstream of CPP32-like activity in mice. 1056 69


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