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)

Human Fas ligand (L) (CD95L) and tumor necrosis factor (TNF)-alpha undergo metalloproteinase-mediated proteolytic processing in their extracellular domains resulting in the release of soluble trimeric ligands (soluble [s]FasL, sTNF-alpha) which, in the case of sFasL, is thought to be implicated in diseases such as hepatitis and AIDS. Here we show that the processing of sFasL occurs between Ser126 and Leu127. The apoptotic-inducing capacity of naturally processed sFasL was reduced by >1,000-fold compared with membrane-bound FasL, and injection of high doses of recombinant sFasL in mice did not induce liver failure. However, soluble FasL retained its capacity to interact with Fas, and restoration of its cytotoxic activity was achieved both in vitro and in vivo with the addition of cross-linking antibodies. Similarly, the marginal apoptotic activity of recombinant soluble TNF-related apoptosis-inducing ligand (sTRAIL), another member of the TNF ligand family, was greatly increased upon cross-linking. These results indicate that the mere trimerization of the Fas and TRAIL receptors may not be sufficient to trigger death signals. Thus, the observation that sFasL is less cytotoxic than membrane-bound FasL may explain why in certain types of cancer, systemic tissue damage is not detected, even though the levels of circulating sFasL are high.
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PMID:Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. 954 32

While the fas/fas ligand system has been extensively investigated in immuno-competent cells, the place of this system in the physiology and pathophysiology of liver cells remains to be clarified. Although we know that fas is present at the surface of hepatocytes--the main hepatic cells--the role of this membranous protein in physiological conditions is not yet elucidated. However it is the localization of fas on the plasma membrane of hepatocytes which explains why these cells are mainly destroyed by apoptosis--in a picture resembling human fulminant hepatitis--when mice are administered with anti-fas antibodies or fas ligand. It is also established that fas is surexpressed in some human chronic liver diseases, such as those induced by hepatitis B or C virus, a situation which could explain the pathogenesis of some liver lesions occurring during these diseases, such as the apoptosis of hepatocytes in piecemeal necrosis. Finally the fact that caspases, a group of cysteine proteases activated in fas-induced apoptosis, opens the way to inhibition of these enzymes by synthetic peptides and to prevent and treat hepatocyte apoptosis. Demonstration of this possibility has been recently reported in animals presenting fulminant hepatitis induced by anti-fas antibodies.
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PMID:Fas-mediated apoptosis of hepatic cells. 985 84

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

NFkappaB is an essential survival factor in several physiological conditions such as embryonal liver development and liver regeneration. However, NFkappaB is also a main mediator of the cellular response to a variety of extracellular stress stimuli, and it has been shown that some viral-induced host cell apoptosis appears to be dependent on NFkappaB activation. The activation of NFkappaB upon viral infection may be a rapid way of initiating an innate immune response against the viral particles. We have assessed the role of NFkB during the early phase of adenoviral hepatitis in a nude mouse model using an adenoviral vector expressing a mutant form of IkappaBalpha. Administration of a LacZ-expressing adenoviral vector induces NFkB DNA and correlates with the up-regulation of Fas (CD95) mRNA, but not FasL (CD95L) mRNA, during the early phase of adenoviral hepatitis. The rapid increase in NFkappaB DNA binding after adenoviral infection of the liver could be very effectively inhibited by IkappaBalpha. Compared with the LacZ control virus, the IkappaBalpha-expressing adenoviral vector inhibits the increase of Fas (CD95) mRNA expression, in particular in the very early phase of the hepatitis. Reporter gene experiments in hepatoma cell lines with a Fas promoter-luciferase construct indicated that the repression of Fas (CD95) mRNA by IkappaBalpha was transcriptionally mediated. The functional relevance of the NFkappaB-dependent increase in Fas (CD95) transcription was assessed by caspase 3 assays and terminal dUTP nick-end labeling tests. Compared with the control, IkappaBalpha adenoviral infection resulted in reduced caspase 3 activity during the early phase of viral hepatitis and in a prevention of liver cell apoptosis 24 h after adenoviral administration. Therefore our study demonstrates a new pro-apoptotic function of NFkappaB in Fas (CD95)-mediated apoptosis of hepatocytes. Interestingly, NFkappaB mediates liver cell apoptosis upon viral infection even in a phase where tumor necrosis factor-alpha is already induced, as shown by the time curves of tumor necrosis factor-alpha serum levels. Therefore, the pro- or anti-apoptotic role of NFkappaB appears to be more determined by the nature of the death stimulus than by the origin of the tissue.
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PMID:NFkappaB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis. 1069 45

Acid sphingomyelinase (ASM) is reported to have an essential function in stress-induced apoptosis although the physiological function of ASM in receptor-triggered apoptosis is unknown. Here, we delineate a pivotal role for ASM in CD95-triggered apoptosis of peripheral lymphocytes or hepatocytes in vivo. We employed intravenous injection of anti-CD4 antibodies or phytohemagglutinin that was previously shown to result in apoptosis of peripheral blood lymphocytes or hepatocytes via the endogenous CD95/CD95 ligand system. Our results demonstrate a high susceptibility in normal mice whereas ASM knock-out mice fail to immunodeplete T cells or develop autoimmune-like hepatitis. Likewise, ASM-deficient mice or hepatocytes and splenocytes ex vivo manifest resistance to anti-CD95 treatment. These results provide in vivo evidence for an important physiological function of ASM in CD95-induced apoptosis.
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PMID:CD95-mediated apoptosis in vivo involves acid sphingomyelinase. 1086 1

Physalis species is a popular folk medicine used for treating cancer, leukemia, hepatitis and other diseases. Studies have shown that the ethanol extract of Physalis peruviana (EEPP) inhibits growth and induces apoptotic death of human Hep G2 cells in culture, whereas proliferation of the mouse BALB/C normal liver cells was not affected. In this study, we performed detailed studies to define the molecular mechanism of EEPP-induced apoptosis in Hep G2 cells. The results further confirmed that EEPP inhibited cell proliferation in a dose- and time-dependent manner. At 50 microg/ml, EEPP significantly increased the accumulation of the sub-G1 peak (hypoploid) and the portion of apoptotic annexin V positive cells. EEPP was found to trigger apoptosis through the release of cytochrome c, Smac/DIABLO and Omi/HtrA2 from mitochondria to cytosol and consequently resulted in caspase-3 activation. Pre-treatment with a general caspase inhibitor (z-VAD-fmk) prevented cytochrome c release. After 48 h of EEPP treatment, the apoptosis of Hep G2 cells was found to associate with an elevated p53, and CD95 and CD95L proteins expression. Furthermore, a marked down-regulation of the expression of the Bcl-2, Bcl-XL and XIAP, and up-regulation of the Bax and Bad proteins were noted. Taken together, the present results suggest that EEPP-induced Hep G2 cell apoptosis was possibly mediated through the CD95/CD95L system and the mitochondrial signaling transduction pathway.
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PMID:Physalis peruviana extract induces apoptosis in human Hep G2 cells through CD95/CD95L system and the mitochondrial signaling transduction pathway. 1548 39

Massive liver cell death provoked in silica-treated mice subsequently infected with herpes simplex virus (HSV)-1 is very similar pathohistologically to the cell death observed in human fulminant hepatitis. Previously, we have shown this liver cell death to be extensive apoptosis. In the present study, we examined various factors related to liver damage patho- and immunologically, as well as by reverse transcription-polymerase chain reaction. Tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), interferon (IFN)-alpha, and interleukin-6 mRNAs were detected to a much greater extent in silica-treated mice compared with control mice after HSV-1 infection, and excessive expression of iNOS mRNA and cytokine mRNAs in the liver may be closely related to massive liver cell apoptosis. The apoptosis was less related to the fas ligand than to TNF-alpha. Silica blockage of macrophages makes the liver cell extremely vulnerable to HSV-1 infection, and it induced expression of E-selectin and neutrophil margination in the liver. Subsequent HSV-1 infection induced excessive production of iNOS and cytokines, particularly TNF-alpha, but administration of anti-TNF-alpha antibody or NG-monomethyl-L-arginine was not completely efficacious for the survival of the mice. Overproduction of free radicals in combination with cytokines, such as TNF-alpha, IL-6 and IFN-alpha, may result in hepatic cell apoptosis.
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PMID:Pathogenesis of herpes simplex hepatitis in macrophage-depleted mice: possible involvement of tumor necrosis factor-alpha and inducible nitric oxide synthase in massive apoptosis. 1633 16

Interferon-gamma (IFNgamma) is a central component of the complex cytokine and inflammatory response that contributes to liver cell injury in hepatitis. We report that in the primary hepatocyte IFNgamma synergizes with the mechanistically distinct apoptotic stimuli CD95, tumour necrosis factor-alpha (TNFalpha) and UV-irradiation. For the first time in primary hepatocytes, we show that IFNgamma-mediated apoptotic signalling requires the cell surface interaction of CD95 and its ligand, and we demonstrate that IFNgamma induces soluble CD95 ligand release from hepatocyte monolayers. Utilizing c-myc phosphorothioate antisense fragments, we suppresses hepatocyte apoptosis induced by IFNgamma. In summary, we identify apoptotic pathways that contribute to IFNgamma-mediated cell death. The hepatocellular response to IFNgamma signalling can be modulated by cytokines and by the interruption of CD95 interaction with its ligand. We present evidence to suggest that c-myc contributes to IFNgamma signalling.
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PMID:c-Myc partially mediates IFNgamma-induced apoptosis in the primary hepatocyte. 1750 42

Fas ligand (FasL, CD95L) is a 40-kDa type II transmembrane protein that binds to Fas (CD95) receptors and promotes programmed cell death. Fas receptors are expressed at higher levels in many tumors than in normal cells; however, systemic administration of FasL or agonistic anti-Fas antibodies to mice with tumors caused lethal hepatitis. Somewhat paradoxically, elimination of Fas or FasL from tumors also leads to death induced by CD95 receptor/ligand elimination (DICE). At face value, this suggests that Fas signaling not only kills normal cells, but that it also is essential for tumor cell survival. Targeting this pathway may not only fail to kill tumors, but instead may even enhance their growth, leading some to report the demise of Fas ligand in cancer immunotherapy. But, to paraphrase Mark Twain, is this death an exaggeration? Here, we provide a careful examination of the literature exploring the merits of FasL as a novel form of cancer immunotherapy. With local administration using delivery vectors that achieve high levels of expression in the tumor environment, our results indicate that the potential for systemic toxicity is eliminated in higher mammals, and that a systemic anti-tumor response ensues, which delays or prevents progression and simultaneously attacks distant metastases.
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PMID:Fas ligand based immunotherapy: A potent and effective neoadjuvant with checkpoint inhibitor properties, or a systemically toxic promoter of tumor growth? 2701 Oct 46

CD95/Fas ligand (FasL) is a cell death-promoting member of the tumor necrosis factor family with important functions in the regulation of T-cell homeostasis and cytotoxicity. In T cells, FasL expression is tightly regulated on a transcriptional level involving a complex set of different transcription factors. The orphan nuclear receptor liver receptor homolog-1 (LRH-1/NR5a2) is involved in the regulation of development, lipid metabolism and proliferation and is predominantly expressed in epithelial tissues. However, its expression in T lymphocytes has never been reported so far. Based on in silico analysis, we identified potential LRH-1 binding sites within the FASLG promoter. Here, we report that LRH-1 is expressed in primary and secondary lymphatic tissues, as well as in CD4+ and CD8+ T cells. LRH-1 directly binds to its binding sites in the FASLG promoter, and thereby drives FASLG promoter activity. Mutations in the LRH-1 binding sites reduce FASLG promoter activity. Pharmacological inhibition of LRH-1 decreases activation-induced FasL mRNA expression, as well as FasL-mediated activation-induced T-cell apoptosis and T-cell cytotoxicity. In a mouse model of Concanavalin A-induced and FasL-mediated hepatitis pharmacological inhibition of LRH-1 resulted in decreased hepatic FasL expression and a significant reduction of liver damage. In summary, these data show for the first time LRH-1 expression in T cells, its role in FASLG transcription and the potential of pharmacological inhibition of LRH-1 in the treatment of FasL-mediated immunopathologies.
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PMID:Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions. 2840 81


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