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

Cyclooxygenase (COX) is the key enzyme for prostaglandin (PG) synthesis. PGs are mediators of many critical physiological and inflammatory responses. There are two isoforms, COX-1 and COX-2, both of which are constitutively expressed in the central nervous system (CNS). Studies have shown that COX-1 and COX-2 are involved in physiological and pathological conditions of the brain. However, little is known about the role(s) of COX in the host defense system against a viral infection in the CNS. In this report, we used Vesicular Stomatitis Virus (VSV) induced acute encephalitis to distinguish between the contribution(s) of the two isoforms. COX-2 activity was inhibited with a COX-2 selective drug, celecoxib (Celebrex), and COX-1 was antagonized with SC560. We found that inhibition of COX-2 led to decreased viral titers, while COX-1 antagonism did not have the same effect at day 1 post infection. 5-lipooxygenase (5-LO) expression and neutrophil recruitment in the CNS were increased in celecoxib-inhibited mice. Furthermore, mice treated with celecoxib expressed more Nitric Oxide Synthase-1 (NOS-1), a crucial component of the innate immune system in the restriction of VSV propagation. The expression of type 1 cytokines, IFN-gamma and IL-12, were also increased in celecoxib-treated mice.
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PMID:Selective inhibition of COX-2 is beneficial to mice infected intranasally with VSV. 1193 20

Potentiation of 5-fluorouracil/leucovorin (FUra/LV) cytotoxicity by IFN-gamma in colon carcinoma cells is dependent on FUra-induced DNA damage, the Fas death receptor, and independent of p53 and RNA-mediated FUra toxicity, which occurs in normal gastrointestinal tissues. This provides a rationale for enhancing the selective action of FUra/LV by IFN-gamma in the treatment of colorectal carcinoma. Based on results from our preclinical studies we designed a Phase I trial combining FUra (370 mg/m2) and LV (200 mg/m2), i.v. bolus daily x 5 days, with escalating doses of IFN-gamma (10-100 micro g/m2) s.c. on days 1, 3, and 5, every 28 days. Twenty-five patients with carcinomas were enrolled; 6 patients received IFN-gamma on days 1 and 3 only. The dose-limiting toxicity, stomatitis, occurred most frequently at 100 micro g/m2 IFN-gamma. Minor response or SD was observed in 2 of 9 patients and in 4 of 12 patients at dose levels of < or =50 micro g/m2 and > or =75 micro g/m2 IFN-gamma, respectively. Three evaluable chemonaive patients demonstrated partial response (2) or complete response (1). Serial plasma samples revealed peak FUra concentrations of >100 micro M; at 100 micro g/m2 IFN-gamma plasma concentrations >5 units/ml persisted for 6.5 h and >1 unit/ml for 28.5 h. The pharmacokinetic parameters of IFN-gamma correlated with a 2-3-fold up-regulation of Fas expression at 24 h in CD15+ cells in peripheral blood samples. Furthermore, clinically relevant IFN-gamma concentrations up-regulated Fas expression and sensitized HT29 colon carcinoma cells in vitro to FUra/LV cytotoxicity. On the basis of the modulation of Fas signaling, FUra/LV combined with IFN-gamma has shown activity in a Phase I trial in colorectal carcinoma and warrants additional evaluation in Phase II.
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PMID:Modulation of the Fas signaling pathway by IFN-gamma in therapy of colon cancer: phase I trial and correlative studies of IFN-gamma, 5-fluorouracil, and leucovorin. 1217 74

Using infections with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus in mice as model systems, we have investigated the ability of antigen-primed CD8+ T cells generated in the context of viral infections to produce IL-2. Our results indicate that acute immunizing infection normally leads to generation of high numbers of IL-2-producing antigen-specific CD8+ T cells. By costaining for IL-2 and IFN-gamma intracellularly, we found that IL-2-producing cells predominantly constitute a subset of cells also producing IFN-gamma. Comparison of the kinetics of generation revealed that IL-2-producing cells appear slightly delayed compared with the majority of IFN-gamma producing cells, and the relative frequency of the IL-2-producing subset increases with transition into the memory phase. In contrast to acute immunizing infection, few IL-2-producing cells are generated during chronic LCMV infection. Furthermore, in MHC class II-deficient mice, which only transiently control LCMV infection, IL-2-producing CD8+ T cells are initially generated, but by 4 weeks after infection this subset has nearly disappeared. Eventually the capacity to produce IFN-gamma also becomes impaired, while cell numbers are maintained at a level similar to those in wild-type mice controlling the infection. Taken together, these findings indicate that phenotyping of T cell populations based on capacity to produce cytokines, and especially IL-2, can provide important information as to the functional status of the analysed cell subset. Specifically, combined analysis of the capacity to produce IL-2 and IFN-gamma can be used as a predictor for loss of function within the CD8+ T cell compartment.
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PMID:High numbers of IL-2-producing CD8+ T cells during viral infection: correlation with stable memory development. 1218 65

Hepatitis C virus (HCV), especially the genotype 1, is naturally resistant to the antiviral effects of interferon-alpha (IFN-alpha). Expression of the whole HCV genome and the NS5A protein has been suggested to interfere with the antiviral activity of IFN-alpha. Here we have analyzed the effect of individual or various combinations of HCV proteins on IFN-alpha-mediated antiviral effect against vesicular stomatitis virus (VSV). When the structural proteins (core-E1-E2) of HCV genotype 1 were expressed in human osteosarcoma cells in a tetracycline-regulated manner, partial VSV resistance to IFN-alpha was established. This was seen as an enhancement of both viral protein synthesis and production of infectious virus. Priming of core-E1-E2-expressing cells with low doses of IFN-gamma (10 IU/ml) partially restored the antiviral activity of IFN-alpha. The core (high-level expression) and NS4B protein expression also showed some rescue of VSV replication. In this model cell system NS3A-NS4A complex and NS5A showed no inhibition of IFN-alpha-induced antiviral activity. Our results indicate that the expression of structural proteins of HCV may impair the antiviral activity of IFNs.
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PMID:Expression of HCV structural proteins impairs IFN-mediated antiviral response. 1220 19

Interferon (IFN)-gamma, is not only a marker of T(H)1 CD4, CD8 and natural killer (NK) cells, it is also a critical antiviral mediator which is central to the elimination of viruses from the CNS. In this review, we describe IFN-gamma, its receptor, signal transduction from receptor engagement, and antiviral downstream mediators. We demonstrate that although neurons are post-mitotic and non-renewing, they respond to IFN-gamma in a fashion similar to peripheral fibroblasts or lymphocytes. We have illustrated this review with details about studies on the role(s) of IFN-gamma in the pathogenesis of measles virus (MV), herpes simplex virus (HSV) type 1, and vesicular stomatitis virus (VSV) infections of the CNS. For VSV infection, IFN-gamma signals through Jaks 1 and 2 and STAT1 to activate (interferon regulatory factor) IRF-1; although viral protein synthesis is inhibited, PKR is not a critical mediator in the antiviral response to VSV in murine neurons. In contrast, induction of nitric oxide synthase (NOS) type 1 and its production of nitric oxide is essential in the elimination of viruses from neurons.
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PMID:The role of IFN-gamma in immune responses to viral infections of the central nervous system. 1240 79

Cardiac antigen-specific CD8(+) T cells are involved in the autoimmune component of human myocarditis. Here, we studied the differentiation and migration of pathogenic CD8(+) T cell effector cells in a new mouse model of autoimmune myocarditis. A transgenic mouse line was derived that expresses cardiac myocyte restricted membrane-bound ovalbumin (CMy-mOva). The endogenous adaptive immune system of CMy-mOva mice displays tolerance to ovalbumin. Adoptive transfer of naive CD8(+) T cells from the ovalbumin-specific T cell receptor-transgenic (TCR-transgenic) OT-I strain induces myocarditis in CMy-mOva mice only after subsequent inoculation with ovalbumin-expressing vesicular stomatitis virus (VSV-Ova). OT-I effector T cells derived in vitro in the presence or absence of IL-12 were adoptively transferred into CMy-mOva mice, and the consequences were compared. Although IL-12 was not required for the generation of cytolytic and IFN-gamma-producing effector T cells, only effectors primed in the presence of IL-12 infiltrated CMy-mOva hearts in significant numbers, causing lethal myocarditis. Furthermore, analysis of OT-I effectors collected from a mediastinal draining lymph node indicated that only effectors primed in vitro in the presence of IL-12 proliferated in vivo. These data demonstrate the importance of IL-12 in the differentiation of pathogenic CD8(+) T cells that can cause myocarditis.
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PMID:IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis. 1261 21

The natural antiviral immunity of human lymphocytes, leukocytes from peripheral blood and whole-blood cultures was studied using the method of infection with two viruses belonging to different taxonomic groups, vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). The kinetics of virus replication in the kinds of cultures and the dependence of culture infection on pre-infection incubation time were studied. When the cultures were infected immediately after preparation, most of them were found to be resistant to the viruses. However, when they were infected after several (1-5) days of incubation, VSV and EMCV multiplied in the cultures to high titers. The time of losing resistance was individually differentiated. The results indicate the presence of a non-specific antiviral immunity characteristic for individuals. The antiviral immunity of healthy donors was compared with that of people suffering from recurrent infections of the upper respiratory tract. This latter group expressed statistically significant lower innate immunity than healthy donors. However, there were no differences in interferon (IFN) and tumor necrosis factor (TNF) production between these groups. In order to examine the contribution of the endogenous IFNs and TNF-alpha in maintaining innate immunity, specific antibodies against IFN-alpha, IFN-beta, IFN-gamma and TNF-alpha were added to VSV-infected leukocytes resistant to infection. The antibodies reduced the antiviral resistance in 9 of 16 experiments. The results suggest that both endogenous interferons and TNF-alpha may participate in the constitution of innate immunity, though they are not the only mediators of it.
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PMID:Individual differentiation of innate antiviral immunity in humans; the role of endogenous interferons and tumor necrosis factor in the immunity of leukocytes. 1269 4

In this report, the signaling pathways utilized by interferon (IFN)-gamma in neurons and their respective roles in the inhibition of vesicular stomatitis virus (VSV) replication were studied. The authors have previously shown that IFN-gamma treatment of NB41A3 neuroblastoma cells results in a 2-log inhibition of VSV production. This inhibition of VSV replication is dependent both in vitro and in vivo on nitric oxide (NO) production by NO synthase (NOS)-1. In NB41A3 neuroblastoma cells, IFN-gamma was found to induce the signal transducer and activator of transcription (STAT) STAT1 phosphorylation, interferon regulatory factor (IRF)-1 expression, and p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation; MAPK, however, was not required for inhibition of viral replication. Using olfactory bulb-enriched primary neuronal cultures, the inhibition of VSV replication was found to be STAT1 dependent, but did not require IRF-1.
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PMID:Interferon-gamma-induced inhibition of neuronal vesicular stomatitis virus infection is STAT1 dependent. 1498 29

The ability of virus-specific CD8(+) T cells to produce cytokines was studied in mice infected with lymphocytic choriomeningitis virus and vesicular stomatitis virus. Intracellular staining was used to visualize cytokine-producing CD8(+) and CD4(+) T cells. Overall, virus-specific CD8(+) T cells produce a similar range of cytokines (IFN-gamma, TNF-alpha, IL-2, GM-CSF, RANTES, MIP-1alpha and MIP-1beta) as CD4(+) T cells, but the relative distribution of cytokine-producing subsets is different. Moreover, cytokine-producing CD8(+) T cells were found to dominate numerically at all time-points tested. Co-staining for more than one cytokine revealed that while all cytokine-producing CD8(+) T cells synthesized IFN-gamma, additional cytokines were produced by partly overlapping subsets of this population. The frequency of cells producing more than one cytokine was higher in a tertiary site (peritoneum) and generally increased with transition into the memory phase; however, GM-CSF producing cells were only present transiently. Concerning factors predicted to influence the distribution of cytokine-producing subsets, IFN-gamma and IL-12 did not play a role, nor was extensive virus replication essential. Notably, regarding the heterogeneity in cytokine production by individual cells with similar epitope specificity, variation in TCR avidity was not the cause, since in vivo-activated TCR transgene-expressing cells were as heterogeneous in cytokine expression as polyclonal cells specific for the same epitope.
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PMID:Cytokine production by virus-specific CD8(+) T cells varies with activation state and localization, but not with TCR avidity. 1516 55

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


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