Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of nitric oxide synthase (NOS) in host defense and clearance of vesicular stomatitis virus (VSV) from the central nervous system (CNS) was examined. NOS-1, NOS-2, and NOS-3 knockout mice were infected with VSV and were treated with either IL-12 or medium. IL-12 treatment resulted in substantially decreased VSV titers in wildtype and NOS-3 knockout mice, but had a marginal effect in the NOS-1 and NOS-2 knockout mice. NOS-1 expression in neurons was associated with survival from VSV infection. The data indicate that the enzyme activity is local, since NOS-2 expression in microglia and inflammatory macrophages and NOS-3 expression in astrocytes, endothelial cells, and ependymal cells did not compensate.
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PMID:Neuronal expression of NOS-1 is required for host recovery from viral encephalitis. 1036 76

In this report, the role of nitric oxide synthase (NOS) and IL-12 administration in inhibition of vesicular stomatitis virus (VSV) from infected neuroblastoma cells was examined. We previously have shown that cytokine treatment of cells results in the induction of NOS-1, and this is associated with a 2 log inhibition of VSV production. We performed these studies to examine the mechanism by which viral replication is suppressed. Neuroblastoma cells (NB41A3) were treated with either IL-12 or medium and subsequently infected with VSV. Viral protein and mRNA were isolated from these cells, and their levels were measured by Western or Northern blots, respectively. mRNA levels were decreased modestly, but viral proteins were decreased substantially in cells pretreated with IL-12, suggesting that the inhibitory effect of NO is working at the translational level. Cytokine treatment of cells was not associated with oxidative stress. The viral proteins also were nitrosylated. These data suggest that the mechanism of NO inhibition of viral replication occurs through translational interference and posttranslational modifications of viral components.
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PMID:Mechanisms of cytokine-mediated inhibition of viral replication. 1038 58

Intranasal infection of mice by Vesicular Stomatitis Virus (VSV) often leads to breakdown of the blood-brain barrier (BBB). The role of Interleukin 12 (IL-12) and nitric oxide synthase (NOS) was examined here. Wild-type (WT), NOS-1 knockout (KO), and NOS-3 KO mice were infected with VSV and treated with either IL-12 or medium. IL-12 treatment of uninfected hosts did not result in pathology. In contrast with WT and NOS-1 KO mice, where extensive gross and ultrastructural correlation of BBB breakdown were evident following infection, in NOS-3 KO mice, integrity of the BBB was observed. Thus NOS-3 activity in astrocytes, endothelial cells, or ependymal cells may play an essential role in regulating the BBB.
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PMID:Regulation of the BBB during viral encephalitis: roles of IL-12 and NOS. 1044 72

Cyclooxygenase (COX) is the key enzyme in the conversion of arachidonic acid to prostaglandins. COX has two isoforms: COX-1, the constitutively expressed form, and COX-2, the inducible form. Prostaglandins are mediators of many critical physiological and inflammatory responses, but little is known about their roles during a viral infection in the central nervous system (CNS). We used non-selective inhibitors of COX, aspirin and indomethacin, and a selective antagonist of COX-2, celecoxib, to study the role of prostaglandins in Vesicular Stomatitis Virus (VSV) induced encephalitis. We found that the inhibition of COX antagonizes VSV propagation both in vitro and in vivo. In addition, aspirin and celecoxib both prevented the disruption of the blood brain barrier in VSV-infected mice. In vitro experiments showed that the effect of COX inhibition was at least partially mediated by increased production of Nitric Oxide (NO), a molecule known to inhibit VSV replication. When NO production was inhibited by N(omega)-nitro-L-methyl-arginine-ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, the difference in viral titer between aspirin (or celecoxib)-treated and the control cells was abolished. VSV-infected mice treated with celecoxib expressed more NOS-1 and produced more NO in their CNS compared to the controls. Our data suggest that the product(s) of COX have antagonistic effect(s) on NO production in the mouse CNS.
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PMID:NSAID treatment suppresses VSV propagation in mouse CNS. 1102 93

In this report, the role of STAT4 and local production of interleukin (IL)-12 in the central nervous system (CNS) were examined during experimental vesicular stomatitis virus (VSV) encephalitis. We have previously shown that IL-12 treatment is beneficial both in vitro and in vivo during experimental VSV infection. This inhibition of VSV replication was dependent on the production of nitric oxide (NO) by the neuronal isoform of nitric oxide synthase (NOS-1). In vitro, IL-12 induces the phosphorylation and nuclear localization of STAT4 in neuroblastoma cell lines. STAT4 expression was not required for host survival or clearance of virus during experimental VSV encephalitis. Taken together, these data suggest that while neurons can respond directly to IL-12 in vitro by signaling through STAT4, STAT4 is not required for survival. It is likely that redundant innate host inflammatory cytokine responses compensate for the absence of IL-12 signaling.
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PMID:IL-12, while beneficial, is not essential for the host response to VSV encephalitis. 1245 40

In this report, the mechanism through which interferon-gamma (IFN-gamma) regulates the expression of nitric oxide synthase (NOS-1) in neurons was examined. We have shown previously that IFN-gamma treatment of cells results in a two log inhibition of vesicular stomatitis virus (VSV) production. This inhibition of VSV replication is dependent both in vitro and in vivo on nitric oxide (NO) production by NOS-1. Furthermore, this effect is associated with the increased expression and activity of NOS-1 following IFN-gamma treatment. In vitro, exposure to IFN-gamma prior to infection with VSV is a prerequisite to establish an effective antiviral state, indicating the necessity for a priming event. Neuroblastoma cells (NB41A3) were treated with IFN-gamma or medium and examined for changes in NOS-1 protein and mRNA expression. NOS-1 protein expression was found to be increased after IFN-gamma treatment, and this was associated with increases in both neosynthesis and NOS-1 protein stability. NOS-1 transcription and mRNA levels were unaffected by IFN-gamma treatment. These data demonstrate that IFN-gamma regulates NOS-1 expression through posttranscriptional and posttranslational mechanisms.
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PMID:Posttranscriptional regulation of neuronal nitric oxide synthase expression by IFN-gamma. 1498 78

Interleukin (IL)-12, a key cytokine bridging innate and acquired immunity, is efficacious in enhancing recovery from experimental vesicular stomatitis virus (VSV) infection of the mouse central nervous system (CNS). This response is associated with the upregulation of neuronal nitric oxide synthase (NOS-1), independent of IFN-gamma and TNF-alpha. We hypothesized that neurons may respond directly IL-12. Our data are consistent with the expression of a functional IL-12 receptor (IL-12R) by neurons in culture and this receptor-ligand interaction results in the induction of an innate antiviral immune response. N18 cells, which did not express IL-12Rbeta2 were transfected with the IL-12Rbeta2 receptor gene; Koch's postulates were fulfilled, as clones derived from this transfection were reconstituted for IL-12 responsiveness.
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PMID:Expression of IL-12 receptor by neurons. 1535 7

Pharmacologic inhibition of the proteasome resulted in increased NOS-1 protein levels and increased NO production by neuronal cells. This correlated with an increased antiviral effect of IFN-gamma against the replication of vesicular stomatitis virus (VSV) replication in vitro. We also observed that a regulatory protein, Protein Inhibitor of NOS-1 (PIN) was down-regulated by IFN-gamma treatment, and more ubiquitinated PIN accumulated in IFN-gamma treated neurons. In cells of the reticuloendothelial system, IFN-gamma treatment induces the expression of a set of low molecular weight MHC-encoded proteins (LMPs), which replace the beta-subunit of the proteasome complex during the proteasome neosynthesis, resulting in a complex termed the immunoproteasome. LMP2, -7, and -10 were induced and the immunoproteasome was generated by IFN-gamma treatment in neuronal cells. Importantly, we observed that IFN-gamma induced inhibition of VSV protein synthesis was not dependent on ubiquitination.
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PMID:The role of the proteasome-ubiquitin pathway in regulation of the IFN-gamma mediated anti-VSV response in neurons. 1695 28

Acute viral infection of neurons presents a difficult problem to the host, since neurons are essential and not replaced, therefore cell-autonomous pathway(s) of suppressing viral replication are critical. We have examined the mechanisms by which neurons respond to exogenous interferons (IFNs) and observed that novel pathways inhibit acute vesicular stomatitis virus (VSV) replication. For both type I (IFN-beta) and Type II (IFN-gamma) interferons, post-translational modification of viral proteins contributed to the replication blockade, diminishing the efficiency of viral assembly and budding from the host neuron. IFN-gamma treatment induces the accumulation of NOS-1 in the absence of an increase of mRNA encoding this enzyme; a NOS-1-inhibiting protein, PIN, is rapidly ubiquitinated and eliminated in the presence of IFN-gamma. NOS-1 produces NO which combines with superoxide to form peroxynitrite (ONOO-), this binds tyrosines, cysteines, and serines; antagonism of NOS-1 with either non-specific or selective inhibitors block the antiviral effect of IFN-gamma. VSV proteins are decorated with -NO(2) in IFN-gamma-treated neurons, probably resulting in their diminished ability to interact properly and mature into budding virus. For IFN-beta, protein phosphorylation of the Matrix protein (M) and Phosphoprotein (P) were altered in infected neurons, with hyperphosphorylation of M (but not hypophosphorylated P) found in released virions. Hyperphosphorylated M protein does not immunoprecipitate with the viral ribonucleoprotein complex in IFN-beta-treated neurons. Thus both types of IFN interfere with viral assembly and release of infectious particles, but by distinct pathways.
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PMID:DISTINCT MECHANISMS OF INHIBITION OF VSV REPLICATION IN NEURONS MEDIATED BY TYPE I AND TYPE II IFN. 2050 25