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)

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

Apoptosis (programmed cell death) has been shown to play a major role in development and in the pathogenesis of numerous diseases. A principal mechanism of apoptosis is molecular interaction between surface molecules known as the "death receptors" and their ligands. Perhaps the best-studied death receptor and ligand system is the Fas/Fas ligand (FasL) system, in which FasL, a member of the tumor necrosis factor (TNF) family of death-inducing ligands, signals death through the death receptor Fas, thereby resulting in the apoptotic death of the cell. Numerous cells in the liver and gastrointestinal tract have been shown to express Fas/FasL, and there is a growing body of evidence that the Fas/FasL system plays a major role in the pathogenesis of many liver and gastrointestinal diseases, such as inflammatory bowel disease, graft vs. host disease, and hepatitis. Here we review the Fas/FasL system and the evidence that it is involved in the pathogenesis of liver and gastrointestinal diseases.
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PMID:Fas and Fas ligand in gut and liver. 1071 54

The present study was carried out to analyze the effects of soyasapogenol A on the liver injury mediated by the immune response in concanavalin A-induced hepatitis in mice. Soyasapogenol A reduced the number of infiltrating inflammatory cells in the liver and significantly lowered the elevated level of plasma tumor necrosis factor-alpha (TNF-alpha) 2 h after concanavalin A treatment, and then markedly reduced the elevated plasma alanine aminotransferase activity and decreased the number of apoptotic bodies in the liver parenchymal cells but not in the sinusoidal cells at 24 h. Since the effect of soyasapogenol A on the elevated plasma TNF-alpha level was not appreciable compared to the preventive effect of soyasapogenol A on the elevated plasma alanine aminotransferase level, these results suggest that soyasapogenol A directly prevents apoptosis of hepatocytes, and secondly, inhibits the elevation of plasma TNF-alpha, which consequently resulted in the prevention of liver damage in the concanavalin A-induced hepatitis model.
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PMID:Protective effects of soyasapogenol A on liver injury mediated by immune response in a concanavalin A-induced hepatitis model. 1072 Jun 49

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

Aminoguanidine is an inhibitor of the inducible form of nitric oxide synthase (iNOS). In the present study, the effect of aminoguanidine on concanavalin A-induced hepatitis was examined. Treatment of mice with concanavalin A (10 mg/kg, i.v.) induced interferon-gamma and iNOS mRNA expression in the liver before the elevation of plasma alanine aminotransferase activity. Immunohistochemical study showed the induction of iNOS protein expression in the area of necrosis. Aminoguanidine (1, 3 and 10 mg/kg, i.p.) inhibited the concanavalin A-induced elevation of alanine aminotransferase activity. Aminoguanidine (10 mg/kg, i.p.) did not inhibit concanavalin A-induced interleukin-2, interferon-gamma, tumor necrosis factor-alpha or iNOS mRNA expression in the liver. The plasma nitrite/nitrate level was elevated at 6 and 24 h after concanavalin A treatment. The elevation of nitrite/nitrate was inhibited by aminoguanidine (10 mg/kg, i.p.). From these results, we conclude that nitric oxide formed by iNOS may be involved in the development of concanavalin A-induced hepatitis.
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PMID:Aminoguanidine prevents concanavalin A-induced hepatitis in mice. 1082 65

In chronic viral hepatitis, autoimmune hepatitis, and some chronic cholestatic liver diseases, T lymphocytes serve as effector cells of the immunostimulatory processes. Cellular interactions of immune cells with extracellular matrix components are regulated primarily via the beta 1 subfamily of integrin receptors. The target epitope of several such integrin receptors is the Arg-Gly-Asp sequence, a cell adhesion motif shared by several matrix-associated adhesive glycoproteins. We review the use of synthetic non-peptidic analogs of RGD in the prevention of immune-mediated, concanavalin A-induced liver damage in mice and in inhibiting the development of liver cirrhosis in rats. The Con A-induced elevation of serum transaminases and tumor necrosis factor-alpha and the infiltration of liver tissue by inflammatory cells were inhibited by pretreatment of the mice with the synthetic RGD mimetics. In rats, the progression of thioacetamide-induced liver cirrhosis was markedly inhibited by the co-administration of the RGD mimetic SF-6,5. The compounds described here may be examined therapeutically for pathological conditions in the liver, manifested as necro-inflammation and fibrosis.
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PMID:Non-peptidic analogs of the cell adhesion motif RGD prevent experimental liver injury. 1090 22

Serum pro- and anti-inflammatory mediators in patients with acute liver diseases were assessed to clarify the clinical significance of these measurements in relation to disease severity. Concentrations of circulating tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10, IL-12, and soluble TNF receptors (sTNFR) p55 and p75 were measured at admission in patients with fulminant hepatitis (FH; n=19), severe acute hepatitis (AHS, n=15), or acute hepatitis (AH, n=7). Serum concentrations of TNF-alpha, IL-10, and sTNFR-55 were significantly higher in patients with FH than in those with AHS (P<.05, <.05, and <.01, respectively) or AH (P<.05). Serum IL-10 and TNF-alpha levels were higher in patients who died of FH (n=13) than in FH survivors (n=6; P<.05). The ratios between TNF-alpha and IL-10 and sTNFR-55 or sTNFR-75 were not valuable in predicting mortality and disease severity. However, both proinflammatory cytokine TNF-alpha and anti-inflammatory cytokine IL-10 levels at admission were associated with fatal outcome among patients with FH.
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PMID:High levels of serum interleukin-10 and tumor necrosis factor-alpha are associated with fatality in fulminant hepatitis. 1097 6

Concanavalin A (ConA)-induced hepatitis is a cell-mediated immunoinflammatory condition similar to human autoimmune hepatitis. We investigated the role of interleukin 12 (IL-12) in hepatitis induced in NMRI and C57/BL6 mice by a single injection of ConA. Recombinant murine IL-12 administered 24 hours and 1 hour prior to ConA exacerbated both transaminase activities in plasma and histologic signs of hepatitis. These markers of liver injury were significantly reduced by prophylactic, but not therapeutic treatment with anti-IL-12 monoclonal antibody (mAb). The disease-modulatory effects of IL-12 and anti-IL-12 mAb were associated with profound and reverse modifications of a ConA-induced increase in the circulating levels of IL-4, IL-6, interferon gamma (IFN-gamma) and tumor necrosis factor (TNF). Relative to control animals receiving ConA alone, the plasma levels of these cytokines were all augmented in IL-12/ConA-treated mice and diminished in anti-IL-12 mAb/ConA-treated mice. Anti-IFN-gamma mAb also impeded the appearance of IL-12/ConA-induced hepatitis. Thus, IL-12-induced production of IFN-gamma might play a role in mediating the hepatitis-inducing effect of ConA. However, IL-12p40-deficient C57/BL6 mice were as susceptible as wild-type controls to the hepatitis-inducing effect of ConA.
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PMID:Murine concanavalin A-induced hepatitis is prevented by interleukin 12 (IL-12) antibody and exacerbated by exogenous IL-12 through an interferon-gamma-dependent mechanism. 1100 16

We recently reported the anti-hepatitis effect of a polysaccharide, designated as the D-fraction, extracted from maitake. Its effect includes immuno-regulating activities. We investigated the effect of the glucan in collagen-induced arthritis (CIA). The D-fraction was administered to CIA mice for 30 consecutive days. Arthritis development was observed from the 4th day after the second immunization. The D-fraction did not have any influence on anti-type II collagen antibodies in blood serum or activated B cells. To determine how cellular immunity may be involved in the development of CIA, ratios of CD4+ T cells and their activated form in the axillary and inguinal lymph node T cells were detected by flow cytometry analysis. The ratios were not different between the D-fraction group and the control group. However, interleukin-1beta, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha productions from splenic macrophages were significantly increased to 2.0, 4.7 and 1.9 times the control group level, respectively. The ratio of macrophages in the whole spleen cells was 2.3 times that of the control group, and their migrating ability was 1.9 times higher. Based on these results, we concluded that the arthritis development induced by D-fraction administration is attributable to the activation of splenic macrophages.
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PMID:Effects of maitake (Grifola frondosa) polysaccharide on collagen-induced arthritis in mice. 1113 30

Surgical biopsies of the liver were obtained from woodchuck hepatitis virus (WHV)-infected neonatal woodchucks at 2 time points before the self-limited or chronic outcomes became obvious by serologic criteria. Following segregation of outcomes, livers were analyzed for intrahepatic type 1 cytokine messenger RNAs (mRNAs) (interleukin 2 [IL-2], interferon gamma [IFN-gamma], tumor necrosis factor-alpha [TNF-alpha]) and leukocyte inflammatory phenotype (IgG+ plasma cells, lysozyme+ macrophages, CD3+ T cells). Baselines were assessed using age-matched uninfected control livers. At week 8 (early acute phase), intrahepatic type 1 cytokine mRNAs were similarly low in both outcome settings and no different from age-matched uninfected controls. This was consistent with the minimal initial viral loads and lack of histologic inflammation at this time. At week 14 (mid-acute phase), changes in viral load between outcome groups related inversely to the intrahepatic inflammatory responses. Animals that eventually became resolved had increased intrahepatic expression of IFN-gamma and TNF-alpha mRNAs and robust inflammation by CD3+ T cells, plasma cells, and macrophages. At the same time point of infection, animals that eventually became chronic carriers had an acute hepatitis involving the same cell types, but at diminished levels, and markedly deficient intrahepatic expression of IFN-gamma and TNF-alpha mRNAs. IL-2 mRNA remained at baseline control levels in both outcome groups. These cotemporal comparisons map a critical deviation in host response to the acute stage of an evolving chronic infection. They strongly suggest that increasing viral load and chronicity as an outcome of neonatal WHV infection result from a temporal deficiency in the acute intrahepatic effector mechanisms mediated by IFN-gamma and TNF-alpha.
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PMID:Pathogenesis of experimental neonatal woodchuck hepatitis virus infection: chronicity as an outcome of infection is associated with a diminished acute hepatitis that is temporally deficient for the expression of interferon gamma and tumor necrosis factor-alpha messenger RNAs. 1117 47


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