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)

Toxoplasmosis has gained particular attention in the AIDS era as the most common opportunistic encephalitis in HIV-infected patients. Since there are important parallels between the human and rodent infection, experimental murine toxoplasmosis is widely used to study the immune reactions to this protozoal parasite. Oral application of low-virulent Toxoplasma (T.) gondii cysts leads to a biphasic disease characterized by an acute, generalized phase followed by a chronic stage confined to the brain, where an encephalitis with persistence of the parasite develops. Immunity to T. gondii is T cell mediated, and there is increasing evidence for a critical role of cytokines for an effective immune response. In order to address the functional role of interferon (IFN)-gamma in toxoplasmosis, we took advantage of mice lacking the IFN-gamma-receptor. Inactivation of the IFN-gamma-receptor rendered mice highly susceptible to T. gondii, and they died of a fulminant acute toxoplasmosis. Among the various organs affected, hepatitis was severe enough to cause death. In contrast to wild type animals, IFN-gamma-receptor-deficient mice were unable to activate their macrophages as evidenced by a lack of major histocompatibility complex (MHC) class II antigen induction and the absence of an upregulation of tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS) mRNA transcripts, two macrophage effector molecules. These observations prompted the investigation of TNF- and TNF-receptor-mediated effects in toxoplasmosis by use of mice deficient in either the TNF-receptor type 1 (TNFR1) and/or the TNF-receptor type 2 (TNFR2). The lethal outcome of T. gondii-infected TNFR1/2- and TNFR1-deficient mice, but not of TNFR2-deficient and wild type animals, illustrated the important role of TNF-alpha and TNFR1-mediated signalling, respectively, in this infection. Histopathology attributed death of TNFR1- and TNFR1/2-deficient mice to a severe, necrotizing encephalitis. Unrestricted intracerebral parasite replication in these strains was associated with reduced numbers of iNOS+ leukocytes and a lack of iNOS mRNA induction in their brains as compared to resistant wild type and TNFR2-deficient mice. To precisely identify the cellular sources of cytokines in the brain, flow cytometry of leukocytes isolated from the brain, in situ hybridization, immunohistochemistry and RT-PCR analysis of cytokine mRNA transcripts of magnetically purified leukocyte populations were performed. These studies disclosed that both CD4+, CD8+ T lymphocytes and macrophages recruited to the brain as well as resident cell populations of the CNS including neurons, astrocytes and microglia contributed to the intracerebral cytokine synthesis. Each population was characterized by a specific cytokine pattern. Interestingly, activation of brain cells is a hallmark of Toxoplasma encephalitis. The marked induction of a variety of immunologically important cell surface molecules as MHC class I and II antigens, cell adhesion molecules and their ligands on microglia points to a particular important role of this cell type for the immune response to T. gondii, since the expression of these molecules is a prerequisite for cellular interactions with T cells. The observation of a prominent interleukin (IL)-10 production in the T. gondii-infected brain initiated studies addressing the function of this powerful immunosuppressive mediator in chronic Toxoplasma encephalitis. Neutralization experiments revealed that IL-10 facilitates persistence of the parasite in the brain by downregulating the intracerebral immune response. On the other hand, IL-10 may exert a regulatory role and may be necessary to prevent immunopathological effects of an uncontrolled immune response. In conclusion, these studies demonstrate the important role of the cytokines IFN-gamma and TNF-alpha and their receptors, respectively, for an effective control of T. gondii. In the CNS, the target organ of the parasite, a
 ...
PMID:[Rudolf-Virchow Prize 1998. Award lecture. Toxoplasmosis: a model infection for studying systemic and intracerebral immune reactions]. 1009 13

Experimental models of sepsis using endotoxin challenges, including studies with sensitized animals with D-galactosamine, have largely contributed to the basic rationale for innovative clinical trials in human septic shock, which have, to date, failed. The ability of these models to reproduce human disease has been highly discussed. We report here that the widely used D-galactosamine/LPS model does not account for septic shock. Treatment with YVAD-CMK, a potent tetrapeptide inhibitor of caspases of the interleukin (IL)-1beta converting enzyme (ICE) family, protects from LPS-induced liver apoptosis and mortality in D-galactosamine-sensitized mice when administered either before or up to 2 h after the lethal challenge. This curative effect is related to complete inhibition of caspase-3 activity in the liver. However, YVAD-CMK does not affect LPS-induced release of IL-1beta and does not protect from a lethal dose of LPS in unsensitized mice. These experiments demonstrate the difference between these two widely recognized experimental models of sepsis. LPS toxicity in D-galactosamine-treated mice, leading to blocked gene transcription, results from tumor necrosis factor (TNF)-alpha-induced caspase-3-dependent liver injury, not from the systemic inflammatory response. These results provide evidence that inhibitors of the ICE caspase family can prevent or even overcome the ongoing hepatic injury induced by TNF-alpha during sepsis, ischemia-reperfusion, or severe hepatitis.
 ...
PMID:LPS challenge in D-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock. 1019 82

Although impaired liver regeneration is thought to be a major cause of death in patients with fulminant hepatitis, the mechanisms are not well defined. Since IL-12 synthesis has been reported to be up-regulated in murine hepatitis virus infection, we studied the influence of continuous IL-12 stimulation on murine liver regeneration using flow cytometric and functional analyses. In non-hepatectomized mice, interestingly, the number of hepatic NK cells was significantly decreased on day 7, after six IL-12 injections, and day 14, after 13 IL-12 injections. The number of hepatic NKT cells was markedly increased on day 7 and day 14 of daily IL-12 treatment. The cytotoxic activity of hepatic lymphocytes against both YAC-1 and p815 cells was enhanced on day 2, after single IL-12 injection, and day 7, after six IL-12 injections. In contrast, hepatic lymphocytes isolated 24 h after partial hepatectomy with IL-12 pretreatment did not show any cytolytic activity against either YAC-1 cells or p815 cells. However, continuous IL-12 stimulation resulted in a significantly higher serum alanine aminotransferase (sALT) level 24 h after the partial hepatectomy as compared with sALT levels in mice subjected to either partial hepatectomy or IL-12 pretreatment alone. On the other hand, the expression of hepatic TNF-alpha mRNA was markedly enhanced by continuous IL-12 stimulation even 24 h after partial hepatectomy, as compared with that in non-treated mice and hepatectomy alone. Simultaneous administration of anti-tumor necrosis factor (TNF)-alpha mAb completely inhibited IL-12-induced in vivo enhancement of liver damage after partial hepatectomy. In conclusion, IL-12 induces the specific cytolytic activity against regenerating hepatocytes in vivo mainly through the enhancement of TNF-alpha synthesis.
 ...
PMID:IL-12 induces specific cytotoxicity against regenerating hepatocytes in vivo. 1033 Feb 71

alpha 1-Acid glycoprotein (AGP) is an acute phase protein produced by hepatocytes. Although its exact biological function remains controversial, it was shown to protect galactosamine-sensitized or normal mice against hepatitis and lethal shock induced by tumor necrosis factor (TNF). Rat-AGP-transgenic mice, constitutively producing several mg AGP per ml serum were tested for their response to a combined challenge with TNF and D-(+)-galactosamine. A previously characterized, single transgenic line (9.5-5) was used. In contrast to our expectations both heterozygous or homozygous transgenic mice were not protected by the endogenously overproduced AGP. However, both transgenic and non-transgenic mice were protected by pretreatment with interleukin-1, an effect which we believe is mediated by the induction of acute phase proteins like AGP. Furthermore, both types of mice were protected by exogenous bovine AGP, suggesting that the lack of protection by endogenous AGP is not because of a repressed response to AGP. Finally, we demonstrate that purified AGP from the serum of transgenic mice is as protective as the AGP from non-transgenic mice or rats. The results suggest that AGP is protective only when its concentration is rapidly induced, perhaps because the endogenous steady state synthesis of AGP, in non-transgenic as well as transgenic mice, is coupled to the production of an AGP-binding factor. This study provides an interesting example of differences in outcome to a lethal challenge between an acute administered and a chronically produced protective protein.
 ...
PMID:High-level constitutive expression of alpha 1-acid glycoprotein and lack of protection against tumor necrosis factor-induced lethal shock in transgenic mice. 1034 51

During the past few years, the biological functions of macrophage migration inhibitory factor (MIF) have been extensively re-evaluated. This has been found to be protein involved in broad-spectrum pathophysiological states as an inflammatory cytokine, pituitary-derived hormone, and glucocorticoid-induced immunomodulator. In this study, we investigated the involvement of this cytokine in the pathogenesis of lethal liver injury. Injecting a small dose of lipopolysaccharide (LPS) into bacille Calmette-Guerin (BCG)-primed Jcl:ICR mice caused a lethal hepatic injury mimicking fulminant hepatitis, in which 8 of 11 mice died within 48 hours (27% survival rate). Massive necrosis of parenchymal hepatocytes with marked mononuclear cell infiltration was observed by histological examination. Immunohistochemical analysis showed that most of the infiltrating mononuclear cells were Kupffer cells, macrophages, and, to a lesser extent, T cells. In parallel, serum aminotransferase and tumor necrosis factor-alpha (TNF-alpha) levels were increased. When an anti-MIF polyclonal antibody (0.3 mg IgG fraction/mouse) was intraperitoneally injected into mice primed with BCG, it protected them from acute hepatic failure (90% survival rate) with concomitant improvement of histological features. Injection of the antibody also suppressed the up-regulation of TNF-alpha and T-cell infiltration induced by LPS. Taken together, these results suggested that treatment with the anti-MIF antibody suppresses the endotoxin-induced fatal hepatic failure by regulating production of inflammatory cytokines and T-cell infiltration.
 ...
PMID:Prevention of lethal acute hepatic failure by antimacrophage migration inhibitory factor antibody in mice treated with bacille Calmette-Guerin and lipopolysaccharide. 1034 18

The administration of concanavalin A (Con A) to mice induces cytokine-dependent hepatitis. In the present study, the effect of glycyrrhizin on Con A-induced hepatitis was examined. Treatment of mice with Con A (0.2 mg/mouse, i.v.) induced elevation of the plasma transaminase activities at 24 h. Mice were treated with glycyrrhizin (100, 200 and 400 mg/kg, i.p.), and glycyrrhizin at the doses of 200 and 400 mg/kg inhibited the Con A-induced elevation of the plasma transaminase activities. At 1 h after Con A treatment, interferon-gamma, tumor necrosis factor-alpha, interleukin-2 and interleukin-6 proteins were released into the plasma. Although treatment with glycyrrhizin at 200 mg/kg inhibited Con A-induced hepatitis, it did not affect the release of any of these Con A-induced cytokines into the plasma. The present results clearly show that glycyrrhizin inhibited Con A-induced hepatitis without affecting cytokine expression.
 ...
PMID:Glycyrrhizin protects mice from concanavalin A-induced hepatitis without affecting cytokine expression. 1040 81

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.
 ...
PMID:Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice. 1048 97

Genetic involvement in type 1 autoimmune hepatitis (AIH) is indicated by a marked female preponderance and strong, well-established, human leukocyte antigen (HLA) associations. These associations, however, are not universal and a number of genes outside the major histocompatibility complex may also play a role in susceptibility to type 1 AIH. Prime candidates at present are those polymorphic genes encoding the proinflammatory and immunoregulatory cytokines. The aim of this study was to investigate, for the first time, 2 members of the interleukin-1 (IL-1) family (IL-1B and IL-1RN), 3 polymorphic sites in the interleukin-10 (IL-10) gene promoter (positions -1082, -819, and -592), and 2 polymorphisms in the tumor necrosis factor-alpha (TNF-alpha) promoter (positions -308 and -238) in type 1 AIH. The study was performed on 2 independently collected DNA banks, each with appropriate controls, and throughout the analysis associations described in the first set were confirmed in the second set. Standard polymerase chain reaction (PCR)-based genotyping techniques were used. Overall there were no significant differences in the distributions of the IL-1B and IL-10 alleles, genotypes, or haplotypes in either study set. In contrast we report a significant association between type 1 AIH and TNF*2 (first set: 34% of controls vs. 49% of patients, Pc =.014 and second set: 26% vs. 56%, P =.00008). However, TNF*2 is found in strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype and stratification analysis indicates that the association with TNF*2 is interdependent with HLA DRB1*0301. This is an indication that there is more than one susceptibility allele for type 1 AIH on chromosome 6p21.3.
 ...
PMID:Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. 1049 33

Lymphocyte infiltration is a manifest feature of hepatitis. To reveal the main site and mechanism of lymphocyte adhesion/extravasation in the hepatic vasculature during inflammation, we morphometrically and histologically analyzed these events in relation to adhesion molecule expression using a murine model of T-cell mediated hepatitis induced by concanavalin A (Con A). Although lymphocyte adhesion was restricted to the sinusoids in untreated mice, it increased in all the segments of porto-sinusoidal-hepatic venous system 8 hours after Con A injection; the number of adhering lymphocytes per unit vascular circumference was the largest in the sublobular veins, relatively large in the central veins and small hepatic veins, and relatively small in the sinusoids and negligible in the portal veins. At 20 hours, extravascular lymphocytes showed similar distribution to lymphocyte adhesion at 8 hours except in the portal veins, around which they were possibly accumulated by the translocation of extrasinusoidal lymphocytes. E-selectin and vascular cell adhesion molecule-1 (VCAM-1) were transiently expressed at 4 to 6 hours, whereas P-selectin and intercellular adhesion molecule-1 were not changed between 0 and 48 hours. In particular, E-selectin expression coincided with that of lymphocyte adhesion in distribution. Lymphocyte attachment was inhibited by pretreatment with anti-E-selectin monoclonal antibody (MAb) or anti-VCAM-1 MAb, and expression of E-selectin and VCAM-1 was suppressed by pretreatment with anti-tumor necrosis factor-alpha (TNF-alpha) MAb. Electron microscopically, lymphocytes were trapped by endothelial lamellipodia and traversed the endothelium by diapedesis. These results indicate that lymphocyte adhesion/transmigration preferentially takes place in the sublobular veins in association with TNF-alpha-induced endothelial activation, i.e., E-selectin and VCAM-1 expression and lamellipodia formation.
 ...
PMID:Sublobular veins as the main site of lymphocyte adhesion/transmigration and adhesion molecule expression in the porto-sinusoidal-hepatic venous system during concanavalin A-induced hepatitis in mice. 1061 32

The role of leptin was investigated in two models of T cell-mediated hepatitis: the administration of Con A or of Pseudomonas aeruginosa exotoxin A (PEA). In both models, leptin-deficient (ob/ob) mice were protected from liver damage and showed lower induction of tumor necrosis factor (TNF) alpha and IL-18 compared with their lean littermates. Neutralization of TNF-alpha reduced induction of IL-18 by either Con A (70% reduction) or PEA (40% reduction). Pretreatment of lean mice with either soluble TNF receptors or with an anti-IL-18 antiserum significantly reduced Con A- and PEA-induced liver damage. The simultaneous neutralization of TNF-alpha and IL-18 fully protected the mice against liver toxicity. However, neutralization of either IL-18 or TNF-alpha did not inhibit Con A-induced production of IFN-gamma. Thymus atrophy and alterations in the number of circulating lymphocytes and monocytes were observed in ob/ob mice. Exogenous leptin replacement restored the responsiveness of ob/ob mice to Con A and normalized their lymphocyte and monocyte populations. These results demonstrate that leptin deficiency leads to reduced production of TNF-alpha and IL-18 associated with reduced T cell-mediated hepatotoxicity. In addition, both TNF-alpha and IL-18 appear to be essential mediators of T cell-mediated liver injury.
 ...
PMID:Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18. 1068 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>