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)

Macrophage infiltration is a constant feature of human virus-infected tissues. However, the in situ functional status of these cells remains undetermined. In order to document an activation of macrophages in virus-infected tissues, the expression of IL-1 beta and IL-6 genes was analyzed using in situ hybridization. Several tissues were studied, as well as infections induced by different viruses: lymph nodes infected by HIV-1 (9 cases) or EBV (one case), lungs infected by CMV (5 cases) or adenovirus (1 case), livers infected by HBV, either chronically (2 cases) or acutely (7 cases presenting a fulminant hepatitis). With the exception of fulminant HBV hepatitis, IL-1 beta and IL-6 genes were expressed in all cases. IL-1 beta and IL-6 genes were usually coordinately regulated, as cells containing IL-1 beta or IL-6 mRNA were present in identical amounts and displayed a similar distribution. Analysis of the location and the morphology of monokine gene-expressing cells indicated that both small macrophages and endothelial cells expressed IL-1 beta and IL-6 genes. However, neither tingible body macrophages present in lymph node follicles nor Kupffer cells expressed these genes at a detectable level. Infected cells themselves were also negative for monokine gene expression. These findings indicate that expression of IL-1 beta and IL-6 genes by reactive cells may play a role in viral spreading limitation as well as virus-induced tissue damage.
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PMID:In vivo expression of IL-1 beta and IL-6 genes during viral infections in human. 165 44

Viral infections result in alterations in hemostasis and coagulation. It has previously been shown that susceptibility to murine hepatitis virus strain 3 (MHV-3), a coronavirus, correlates directly with the spontaneous, T lymphocyte-instructed expression of a procoagulant monokine that exhibits prothrombin-cleaving activity (procoagulant activity [PCA]). A biologic role for PCA in the pathogenesis of MHV-3 infection is suggested by results of in vivo microscopic observations made during acute MHV-3 infection. Recently, it has been demonstrated that prostaglandin E2 abrogates the induction of PCA by MHV-3 both in vivo and in vitro and prevents hepatic necrosis and the associated microcirculatory changes. These data suggest that MHV-3 induces cellular injury through the activation of the coagulation cascade and provide further evidence for a role for PCA in the pathogenesis of MHV-3 infection.
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PMID:Activation of the immune coagulation system by murine hepatitis virus strain 3. 254 45

Induction of a Th1 immune response against viral infection of the CNS is important in contributing to viral clearance. The present studies demonstrate a role for the T cell chemoattractant chemokine Mig (monokine induced by IFN-gamma) in contributing to a Th1 response against mouse hepatitis virus infection of the CNS. Analysis of the kinetics of Mig expression revealed mRNA transcripts present at days 7 and 12 postinfection (p.i.) but not early (day 2) or late (day 35) in the infection. To determine functional significance, mouse hepatitis virus-infected mice were treated with anti-Mig antisera, and the severity of disease was evaluated. Such treatment resulted in a marked increase in mortality that correlated with a >3 log increase in viral burden within the brains as compared with control mice treated with normal rabbit serum. Anti-Mig-treated mice displayed a significant decrease (p < 0.005) in CD4(+) and CD8(+) T cell recruitment into the CNS as compared with normal rabbit serum-treated mice. In addition, anti-Mig treatment resulted in a significant decrease (p < 0.05) in levels of IFN-gamma and IFN-beta that coincided with increased (p < 0.02) expression of the anti-inflammatory Th2 cytokine IL-10 within the CNS. Collectively, these data indicate that Mig is important in contributing to host defense by promoting a protective Th1 response against viral infection of the CNS.
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PMID:Expression of Mig (monokine induced by interferon-gamma) is important in T lymphocyte recruitment and host defense following viral infection of the central nervous system. 1116 Feb 25

Intracerebral infection of mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a chronic demyelinating disease with clinical and histological similarities with the human demyelinating disease multiple sclerosis (MS). Following MHV infection, chemokines including CXC chemokine ligand (CXCL)10 (IFN inducible protein 10 kDa), CXCL9 (monokine induced by IFN-gamma), and CC chemokine ligand 5 (RANTES) are expressed during both acute and chronic stages of disease suggesting a role for these molecules in disease exacerbation. Previous studies have shown that during the acute phase of infection, T lymphocytes are recruited into the CNS by the chemokines CXCL10 and CXCL9. In the present study, MHV-infected mice with established demyelination were treated with antisera against these two chemokines, and disease severity was assessed. Treatment with anti-CXCL10 reduced CD4+ T lymphocyte and macrophage invasion, diminished expression of IFN-gamma and CC chemokine ligand 5, inhibited progression of demyelination, and increased remyelination. Anti-CXCL10 treatment also resulted in an impediment of clinical disease progression that was characterized by a dramatic improvement in neurological function. Treatment with antisera against CXCL9 was without effect, demonstrating a critical role for CXCL10 in inflammatory demyelination in this model. These findings document a novel therapeutic strategy using Ab-mediated neutralization of a key chemokine as a possible treatment for chronic human inflammatory demyelinating diseases such as MS.
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PMID:Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis. 1156 31

IFN-gamma-inducible protein 10 (IP-10, CXCL10), a chemokine secreted from cells stimulated with type I and II IFNs and LPS, is a chemoattractant for activated T cells. Expression of IP-10 is seen in many Th1-type inflammatory diseases, where it is thought to play an important role in recruiting activated T cells into sites of tissue inflammation. To determine the in vivo function of IP-10, we constructed an IP-10-deficient mouse (IP-10(-/-)) by targeted gene disruption. Immunological analysis revealed that IP-10(-/-) mice had impaired T cell responses. T cell proliferation to allogeneic and antigenic stimulation and IFN-gamma secretion in response to antigenic challenge were impaired in IP-10(-/-) mice. In addition, IP-10(-/-) mice exhibited an impaired contact hypersensitivity response, characterized by decreased ear swelling and reduced inflammatory cell infiltrates. T cells recovered from draining lymph nodes also had a decreased proliferative response to Ag restimulation. Furthermore, IP-10(-/-) mice infected with a neurotropic mouse hepatitis virus had an impaired ability to control viral replication in the brain. This was associated with decreased recruitment of CD4(+) and CD8(+) lymphocytes into the brain, reduced levels of IFN-gamma and the IFN-gamma-induced chemokines monokine induced by IFN-gamma (Mig, CXCL9) and IFN-inducible T cell alpha chemoattractant (I-TAC, CXCL11) in the brain, decreased numbers of virus-specific IFN-gamma-secreting CD8(+) cells in the spleen, and reduced levels of demyelination in the CNS. Taken together, our data suggest a role for IP-10 in both effector T cell generation and trafficking in vivo.
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PMID:IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. 1190 72

Chemokines are involved in the pathogenesis of alcoholic hepatitis and are considered to contribute to the migration of leukocytes into the liver during chronic ethanol intoxication. This work tests the hypothesis that chronic ethanol consumption selectively enhances chemokine release by Kupffer cells and hepatic sinusoidal endothelial cells and migration of inflammatory cells into the liver. Furthermore, enhanced hepatic chemokine secretion may induce an autocrine effect on the ability of Kupffer cells and endothelial cells to chemotax and ingest microbial particles. Male Wistar rats were fed with ethanol in agar block and water for 32 weeks, and were allowed free access to solid food. Results show that after 32 weeks of feeding, leukocyte infiltration and steatosis were observed in the livers of ethanol-fed rats. The majority of the infiltrated cells were CD8+ cells. Serum ALT, endotoxin, MIP-1alpha, MCP-1 and RANTES, (but not CINC and MIP-2) were also increased in the ethanol-fed rats than in the pair-fed group. Isolated Kupffer cells from ethanol-fed rats were primed for enhanced MIP-1alpha, MCP-1, and RANTES production in vitro, while the endothelial cells were primed for enhanced MIP-1alpha release only. Chronic alcohol intoxication was also associated with increased basal H2O2 formation, enhanced nuclear translocation and binding of NF-kappaB, AP-1 and MNP-1 in Kupffer Cells. Chronic ethanol feeding significantly enhanced MNP-1 binding, but not those of NF-kappaB and AP-1 in endothelial cells. Concomitantly, chemokine-induced chemotaxis, E.coli phagocytosis and f-met-leu-phe-induced superoxide anion production by Kupffer cells were downregulated in the ethanol-fed group. Taken together these data demonstrate that prolonged alcohol consumption may compromise the host to hepatitis as a result of increased chemokine production and at the same time may suppress the innate immune function of hepatic non-parenchymal cells.
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PMID:Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis. 1204 6

T cell recruitment to the infected liver is an essential step for the efficient elimination of hepatitis viruses. The surface expression of CC chemokine receptor (CCR) 1, CCR4, and CCR5 on peripheral blood T lymphocytes and their responsiveness to the chemokines macrophage inflammatory proteins (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normally T cell-expressed and secreted) was analyzed in patients with chronic hepatitis C and hepatitis B infection and compared with healthy subjects. Although CCR4 surface expression was not altered, hepatitis C virus (HCV)-infected patients had lower proportions of CD8 T cells with CCR1 and CCR5 surface expression (P<.05). Migration of CD8 T cells in response to MIP-1alpha, MIP-1beta, and RANTES was significantly reduced in HCV-infected patients (P<.05). Intracellular CCR1 and CCR5 protein and messenger RNA levels in peripheral blood T cells did not indicate reduced chemokine receptor biosynthesis in hepatitis C infection. Thus, chronic hepatitis C, but not hepatitis B, infection alters surface expression of distinct CCRs, resulting in lower CC chemokine responsiveness.
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PMID:Reduced CC chemokine receptor (CCR) 1 and CCR5 surface expression on peripheral blood T lymphocytes from patients with chronic hepatitis C infection. 1208 29

The impact of L. monocytogenes infection on maternal immune responses as well as on the outcome of pregnancy was studied in a murine model of pregnancy-associated listeriosis. Mice infected i.v. with L. monocytogenes at day 15 of pregnancy showed a significantly impaired bacterial elimination, which resulted in a severe necrotizing hemorrhagic hepatitis. The aggravated course of the infection could be attributed to a suppressed transcription and production of anti-listerial, pro-inflammatory cytokines and chemokines, namely interferon-gamma, tumor necrosis factor, interleukin-12p40, inducible nitric oxide synthase, murine monokine induced by interferon-gamma, and interferon-gamma-inducible protein-10. In addition, listeriosis significantly increased the abortion rate. Infection of the placenta and fetuses was characterized by placental and fetal necrosis with unrestricted bacterial multiplication. A weak transcription of anti-listerial cytokines in the placenta in the absence of a cellular immune response could not prevent the fatal outcome of pregnancy-associated listeriosis.
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PMID:Effects of pregnancy-associated Listeria monocytogenes infection: necrotizing hepatitis due to impaired maternal immune response and significantly increased abortion rate. 1240 62

We have previously shown that IFN-gamma/STAT1 plays an essential role in concanavalin A (ConA)-induced T cell hepatitis via activation of apoptotic signaling pathways. Here we demonstrate that IFN-gamma/STAT1 also plays a crucial role in leukocyte infiltration into the liver in T cell hepatitis. After injection of ConA, leukocytes were significantly infiltrated into the liver, which was suppressed in IFN-gamma(-/-) and STAT1(-/-) mice. Disruption of the IFN regulatory factor-1 (IRF-1) gene, a downstream target of IFN-gamma/STAT1, abolished ConA-induced liver injury and suppressed leukocyte infiltration into the liver. Additionally, ConA injection induced expression of a wide variety of chemokines and adhesion molecules in the liver. Among them, expression of ICAM-1, VCAM-1, monokine induced by IFN-gamma (Mig), CC chemokine ligand-20, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IFN-inducible T cell-alpha chemoattractant (I-TAC), and IFN-inducible protein-10 (IP-10) was markedly attenuated in IFN-gamma(-/-), STAT1(-/-), and IRF-1(-/-) mice. In primary mouse hepatocytes, Kupffer cells, and endothelial cells, in vitro treatment with IFN-gamma activated STAT1, STAT3, and IRF-1, and induced expression of VCAM-1, ICAM-1, Mig, ENA-78, I-TAC, and IP-10 mRNA. Induction of these chemokines and adhesion molecules was markedly diminished in STAT1(-/-) and IRF-1(-/-) hepatic cells compared with wild-type hepatic cells. These findings suggest that in addition to induction of apoptosis, previously well documented, IFN-gamma also stimulated hepatocytes, sinusoidal endothelial cells, and Kupffer cells partly via an STAT1/IRF-1-dependent mechanism to produce multiple chemokines and adhesive molecules responsible for promoting infiltration of leukocytes and, ultimately, resulting in hepatitis.
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PMID:IFN-gamma/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1. 1524 62

T cell-mediated hepatitis is associated with significant morbidity and mortality worldwide. Levels of C-C chemokine ligand 3/macrophage inflammatory protein-1alpha (CCL3/MIP-1alpha) are elevated in the serum of patients with T cell-mediated liver diseases, but its role is not fully understood. Con A-induced hepatitis is a murine liver-specific inflammation mediated by activated T cells and is driven by an up-regulation of the hepatic expression of IFN-gamma. In this study, we have used CCL3/MIP-1alpha gene-deficient mice to examine the role of CCL3/MIP-1alpha in the pathogenesis of Con A-induced hepatitis. We demonstrate a novel pro-inflammatory role for CCL3/MIP-1alpha since CCL3/MIP-1alpha deficiency significantly attenuated hepatic injury, both biochemically and histologically. Moreover, the recruitment of CCR1-expressing CD4(+) T cells to the liver after Con A treatment was strikingly attenuated by CCL3/MIP-1alpha deficiency. Correspondingly, hepatic IFN-gamma produced by the recruited CD4(+) T cells was significantly reduced by CCL3/MIP-1alpha deficiency during Con A-induced hepatitis. Furthermore, treatment of mice with a dual CCR1/CCR5 peptide antagonist, methionylated RANTES, also markedly reduced hepatic injury and decreased the numbers of CD4(+) T cells within the liver producing IFN-gamma during Con A-induced hepatitis. These findings demonstrate that blockade of the CCL3/MIP-1alpha-CCR1 pathway may represent a novel therapeutic target for treating T cell-mediated liver diseases.
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PMID:CCL3/MIP-1alpha is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4(+) T cells to the liver. 1536 7


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