Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Theiler's virus infection in the central nervous system (CNS) induces a demyelinating disease very similar to human multiple sclerosis. We have assessed cytokine gene activation upon Theiler's murine encephalomyelitis virus (TMEV) infection and potential mechanisms in order to delineate the early events in viral infection that lead to immune-mediated demyelinating disease. Infection of SJL/J primary astrocyte cultures induces selective proinflammatory cytokine genes (interleukin-12p40 [IL-12p40], IL-1, IL-6, tumor necrosis factor alpha, and beta interferon [IFN-beta]) important in the innate immune response to infection. We find that TMEV-induced cytokine gene expression is mediated by the NF-kappaB pathway based on the early nuclear NF-kappaB translocation and suppression of cytokine activation in the presence of specific inhibitors of the NF-kappaB pathway. Further studies show this to be partly independent of dsRNA-dependent protein kinase (PKR) and IFN-alpha/beta pathways. Altogether, these results demonstrate that infection of astrocytes and other CNS-resident cells by TMEV provides the early NF-kappaB-mediated signals that directly activate various proinflammatory cytokine genes involved in the initiation and amplification of inflammatory responses in the CNS known to be critical for the development of immune-mediated demyelination.
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PMID:Infection with Theiler's murine encephalomyelitis virus directly induces proinflammatory cytokines in primary astrocytes via NF-kappaB activation: potential role for the initiation of demyelinating disease. 1274 89

The expression of mitogen-activated protein (MAP) kinases, including extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal protein kinase (JNK), and p38, was analyzed in experimental autoimmune encephalomyelitis (EAE) in rats. Western blot analysis showed that the three MAP kinases (phosphorylated ERK (p-ERK), p-JNK, and p-p38) were increased significantly in the spinal cords of rats with EAE at the peak stage as compared with the levels in controls (p<0.05), and both p-ERK and p-JNK declined slightly in the recovery stage of EAE. Immunohistochemistry showed that p-ERK was constitutively expressed in brain cells, including astroglial cells, and showed enhanced immunoreactivity in those cells in EAE, while some T cells and macrophages were weakly immunopositive for p-ERK in EAE lesions. Both p-JNK and p-p38 were intensely immunostained in T cells in EAE lesions, while a few glial cells and astrocytes were weakly positive for both. Taking all these facts into consideration, we postulate that increased expression of the phosphorylated form of each MAP kinase plays an important role in the initiation of acute monophasic EAE. Differential expression of three MAP kinases was discerned in an animal model of human autoimmune central nervous system diseases, including multiple sclerosis.
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PMID:Activation of mitogen-activated protein kinases in experimental autoimmune encephalomyelitis. 1286 79

The double-stranded (ds) RNA-activated protein kinase (PKR) plays an important role in control of viral infections and cell growth. We have studied the role of PKR in viral infection in mice that are defective in the PKR signaling pathway. Transgenic mice were derived that constitutively express a trans-dominant-negative kinase-defective mutant PKR under control of the beta-actin promoter. The trans-dominant-negative PKR mutant expressing transgenic mice do not have a detectable phenotype, similar to observations with PKR knock-out mice. The requirement for PKR in viral pathogenesis was studied by intracerebral infection of mice with a mouse-adapted poliovirus. Histopathological analysis revealed diffuse encephalomyelitis with severe inflammatory lesions throughout the central nervous system (CNS) in infected wild-type mice. In contrast, histopathological evaluation of virus-injected trans-dominant-negative PKR transgenic mice as well as PKR knock-out mice yielded no signs of tissue damage associated with inflammatory host responses. However, the virus did replicate in both models of PKR-deficient mice at a level equal to that observed in wild-type infected mice. Although the results indicate a clear difference in susceptibility to poliovirus-induced encephalitis, this difference manifests clinically as a slight delay in fatal neuropathy in trans-dominant-negative PKR transgenic and PKR knock-out animals. Our observations support the finding that viral-induced PKR activation may play a significant role in pathogenesis by mediating the host response to viral CNS infection. They support PKR to be an effective target to control tissue damage due to deleterious host responses to viral infection.
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PMID:The double-stranded RNA-activated protein kinase mediates viral-induced encephalitis. 1469 65

Intracerebral infection with Theiler's virus induces a demyelinating disease that resembles human MS. In order to delineate the early events in virus-induced inflammatory disease, we have analyzed chemokine gene activation following Theiler's murine encephalomyelitis virus (TMEV) infection. Infection of primary astrocyte cultures results in activation of various chemokine genes (GRO-1, MCP-1, MCP-5, MIP-1alpha, MIP-1beta, MIP-2, RANTES, IP-10 and MCP-3) that are important in the initiation of an inflammatory response. As early as 1-3 h after TMEV infection, chemokine gene expression is strongly activated. In addition, proinflammatory cytokines do not interfere with TMEV-induced chemokine gene expression and some cytokines may function synergistically for virus-induced upregulation of chemokine gene expression. Chemokine gene activation by TMEV appears to be largely independent of the IFNalphabeta pathway and partly dependent on dsRNA-dependent protein kinase (PKR) and MAP kinase pathways. However, TMEV-induced chemokine gene expression is completely dependent on the NFkappaB pathway. These results strongly suggest that the expression of select chemokine genes upon TMEV infection is activated via the NFkappaB pathway, similar to that of proinflammatory cytokine genes, and these cellular gene products appear to synergistically promote inflammatory responses in the CNS.
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PMID:The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler's virus. 1502 72

Increasing evidence suggests that enhanced production of reactive oxygen species (ROS) activates the MAP kinases, c-Jun N-terminal protein kinase (JNK) and mitogen-activated protein kinase MAPK (p38). These phosphorylated intermediates at the stress-activated pathway induce expression of matrix metalloproteinases (MMPs), leading to inflammatory responses and pathological damages involved in the etiology of multiple sclerosis (MS). Here we report that N-acetylcysteine amide (AD4) crosses the blood-brain barrier (BBB), chelates Cu(2+), which catalyzes free radical formation, and prevents ROS-induced activation of JNK, p38 and MMP-9. In the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, oral administration of AD4 drastically reduced the clinical signs, inflammation, MMP-9 activity, and protected axons from demylination damages. In agreement with the in vitro studies, we propose that ROS scavenging by AD4 in MOG-treated animals prevented MMP's induction and subsequent damages through inhibition of MAPK pathway. The low toxicity of AD4 coupled with BBB penetration makes this compound an excellent potential candidate for the therapy of MS and other neurodegenerative disorders.
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PMID:A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis. 1514 17

There is compelling evidence that a unique innate immune response in the CNS plays a critical role in host defense and clearance of toxic cell debris. Although complement has been implicated in neuronal impairment, axonal loss, and demyelination, some preliminary evidence suggests that the initial insult consequently activates surrounding cells to signal neuroprotective activities. Using two different models of experimental autoimmune encephalomyelitis, we herein demonstrate selective C1q complement activation on neuron cell bodies and axons. Interestingly, in brains with chronic but not acute experimental autoimmune encephalomyelitis, C3b opsonization of neuronal cell bodies and axons was consistently associated with robust neuronal expression of one of the most effective complement regulators, decay-accelerating factor (CD55). In contrast, levels of other complement inhibitors, complement receptor 1 (CD35), membrane cofactor protein (CD46), and CD59 were largely unaffected on neurons and reactive glial cells in both conditions. In vitro, we found that proinflammatory stimuli (cytokines and sublytic doses of complement) failed to up-regulate CD55 expression on cultured IMR32 neuronal cells. Interestingly, overexpression of GPI-anchored CD55 on IMR32 was capable of modulating raft-associated protein kinase activities without affecting MAPK activities and neuronal apoptosis. Critically, ectopic expression of decay-accelerating factor conferred strong protection of neurons against complement attack (opsonization and lysis). We conclude that increased CD55 expression by neurons may represent a key protective signaling mechanism mobilized by brain cells to withstand complement activation and to survive within an inflammatory site.
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PMID:Decay-accelerating factor (CD55) is expressed by neurons in response to chronic but not acute autoimmune central nervous system inflammation associated with complement activation. 1569 72

Molecules that regulate encephalitogenic T cells are of interest for multiple sclerosis. In this study we show that protein kinase Ctheta (PKCtheta) is critical for the development of Ag-specific Th1 cells in experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis. PKCtheta-deficient mice immunized with myelin oligodendrocyte glycoprotein failed to develop cell infiltrates and Th1 cytokines in the CNS and were resistant to the development of clinical EAE. CD4 T cells became primed and accumulated in secondary lymphoid organs in the absence of PKCtheta, but had severely diminished IFN-gamma, TNF, and IL-17 production. Increasing Ag exposure and inflammatory conditions failed to induce EAE in PKCtheta-deficient mice, showing a profound defect in the myelin oligodendrocyte glycoprotein-reactive T cell population. These data provide evidence of a pivotal role for PKCtheta in the generation and effector function of autoimmune Th1 cells.
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PMID:Protein kinase Ctheta controls Th1 cells in experimental autoimmune encephalomyelitis. 1630 73

The reversible S-adenosyl-l-homocysteine hydrolase inhibitor DZ2002 [methyl 4-(adenin-9-yl)-2-hydroxybutanoate] suppresses antigen-induced-specific immune responses, particularly type 1 helper T cell (Th1)-type responses. Experimental autoimmune encephalomyelitis (EAE) is thought to be a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of human multiple sclerosis (MS). In this study, we examined the effects of DZ2002 on active EAE induced by myelin oligodendrocyte glycoprotein (MOG) 35-55 in female C57BL/6 mice. Administration of DZ2002 (50 mg/kg/day i.p.) significantly reduced the incidence and severity of EAE, which was associated with the inhibition of MOG35-55-specific T cell proliferation and Th1-type cytokine production. In vitro studies also demonstrated that DZ2002 inhibited anti-CD3/28-induced naive T cell activation concomitant with the down-regulation of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D3, and the up-regulation or protection of the CDK inhibitor p27. These findings highlight the fact that DZ2002 likely prevents EAE by suppressing T cell activation and suggest its utility in the treatment of MS and other Th1-mediated inflammatory diseases.
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PMID:A reversible S-adenosyl-L-homocysteine hydrolase inhibitor ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell activation. 1691 58

Infection of susceptible mice with the DA strain of Theiler's murine encephalomyelitis virus (TMEV) induces a persistent central nervous system infection accompanied by demyelination that resembles multiple sclerosis. In contrast, Theiler's GDVII strain does not persist, because infected animals either clear the virus or die. Previously, the authors have shown that in vitro infection of RAW264.7 macrophages displays a similar strain-dependent outcome, resulting in the establishment of a persistent infection with the DA strain and clearance of the GDVII strain. Here, the authors show that when RAW264.7 cells were infected with both strains, the antiviral response triggered by the GDVII virus interfered with the DA virus' ability to induce a persistent infection. Treatment of cells with 2-aminopurine, a protein kinase R inhibitor, increased GDVII virus yields in contrast to DA virus yields. By comparing the antiviral activity of RAW264.7 macrophages against TMEV, it was found that GDVII-infected macrophages mounted a five times more potent antiviral response than the DA-infected ones, indicating that there are strain-dependent differences in the induction of host innate immune responses. Measurements of interferon (IFN) production confirmed this finding. In addition, it was found that the macrophages' antiviral response is dependent on the multiplicity of infection. The antiviral activity resulting from GDVII-infected macrophages could be partially neutralized with antibodies against IFN-alpha or IFN-gamma, but not with an anti-IFN-beta antibody. Because only a partial neutralization was reached, the authors speculate that apart from the investigated IFNs, other cellular factors contribute to the observed antiviral activity. Taken together, these results demonstrate the importance of host innate immune responses in determining the balance between viral clearance and viral persistence.
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PMID:Theiler's virus strain-dependent induction of innate immune responses in RAW264.7 macrophages and its influence on viral clearance versus viral persistence. 1745 48

Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4(+) T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a gamma-secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using gamma-secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase Ctheta, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.
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PMID:Notch3 inhibition in myelin-reactive T cells down-regulates protein kinase C theta and attenuates experimental autoimmune encephalomyelitis. 1825 Apr 75


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