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)

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease with similarities to multiple sclerosis (MS). It is induced in mice by the transfer of myelin-reactive T cells. Here we demonstrate that IL-12 stimulates myelin-reactive T cells to up-regulate the beta-chemokine receptor, CCR5, in correlation with the acquisition of central nervous system-infiltrating and encephalitogenic properties. These effects of IL-12 are IFN gamma-independent. The CCR5 ligands, RANTES and MIP-1 alpha, are expressed in the spinal cords of mice at EAE onset. Our results suggest that reagents that block CCR5/beta-chemokine interactions and/or antagonize IL-12 might be useful for treatment of autoimmune demyelination.
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PMID:IL-12 dependent/IFN gamma independent expression of CCR5 by myelin-reactive T cells correlates with encephalitogenicity. 1266 54

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

IFN-regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of IFN-induced genes and type I IFN. It has previously been demonstrated that IRF-1-deficient mice show reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by a peptide from myelin basic protein. To further study the role of IRF-1 in brain inflammation, we analyzed EAE induced by immunization with a myelin oligodendrocyte glycoprotein-derived peptide in 129/Sv mice lacking IRF-1. We found that these mice were almost completely resistant to EAE induction and that this unresponsiveness was intrinsically related to the IRF-1 deficiency of the T cells, but not with any other cell type. Furthermore, we show that the amelioration of EAE was associated with increased production of T(h)2-type and decreased production of T(h)1-type cytokines. These results demonstrate that absence of IRF-1 in myelin-specific T cells results in protection from severe EAE and is associated with a skewing of the T cell response towards T(h)2.
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PMID:Protection from autoimmune brain inflammation in mice lacking IFN-regulatory factor-1 is associated with Th2-type cytokines. 1280 24

In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), autoaggressive T cells traffic into the CNS and induce disease. Infiltration of these pathogenic T cells into the CNS has been correlated with the expression of the chemokine IFN-inducible protein (IP)10/CXC chemokine ligand (CXCL)10, a chemoattractant for activated T cells, and its receptor CXCR3, in the CNS of both MS patients and mice with EAE. In the present study, we report that targeted deletion of IP-10 did not diminish the expression, severity, or histopathology of EAE induced by active immunization with 100 micro g of myelin oligodendrocyte glycoprotein peptide (MOG)p35-55. However, we found that IP-10-deficient mice had a lower threshold for expression of disease compared with wild-type littermates. EAE induced by immunization with 5 micro g of MOGp35-55 resulted in more severe disease characterized by a greater number of CNS lesions and infiltrating mononuclear cells in IP-10-deficient mice compared with wild-type controls. IP-10-deficient mice immunized with MOGp35-55 demonstrated increased levels of IFN-inducible T cell alpha-chemokine/CXCL11 mRNA in the CNS and decreased levels of monokine induced by IFN-gamma/CXCL9 mRNA in draining lymph nodes, suggesting differential compensation for loss of IP-10 in lymphoid vs parenchymal tissue compartments. EAE in IP-10-deficient mice induced by low-dose immunization was associated with enhanced Ag-specific Th1 responses in the draining lymph node, which corresponded with diminished lymph node TGF-beta1 expression. Our data demonstrated that IP-10 was not required for the trafficking of pathogenic T cells into the CNS in EAE but played an unexpected role in determining the threshold of disease susceptibility in the periphery.
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PMID:IFN-inducible protein 10/CXC chemokine ligand 10-independent induction of experimental autoimmune encephalomyelitis. 1468 66

We studied the role of 15-deoxy-delta (12,14)-PGJ2 (15d-PGJ2), a macrophage inhibitor with reported therapeutic effects on experimental allergic encephalomyelitis, in human astrocyte activation in vitro. 15d-PGJ2 inhibited a broad range of astrocyte inflammatory gene expression induced by IL-1, including cytokines (TNFalpha and IL-6), chemokines (RANTES/CCL5 and IP-10/CXCL10) and inducible nitric oxide synthase. 15d-PGJ2 inhibited transactivation of NF-kappaB-dependent promoters, as well as p38 and JNK MAPK phosphorylation induced by IL-1, while having no inhibitory effect on IFN-induced Stat signaling pathways. Our results demonstrating 15d-PGJ2-mediated astrocyte deactivation through inhibition of NF-kappaB are similar to those described for macrophages, and add astrocytes as additional targets for this prostaglandin (PG).
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PMID:15-deoxy-delta (12,14)-PGJ2 inhibits astrocyte IL-1 signaling: inhibition of NF-kappaB and MAP kinase pathways and suppression of cytokine and chemokine expression. 1526 71

Tryptophan and its metabolites are of great interest in understanding the pathogenesis of multiple sclerosis (MS). The total levels of tryptophan and its metabolites, kynurenine and kynurenic acid were determined in plasma by capillary liquid chromatography electrospray ionisation tandem mass spectrometry. This is the first report of the plasma levels of these analytes in healthy controls and relapsing-remitting MS patients receiving long-term and acute interferon-beta (IFN-beta) treatment. Twenty-four hours post-administration increased kynurenine levels (first IFN MS versus healthy, P = 0.042) and kynurenine/tryptophan ratio (K/T; first IFN MS versus healthy, P =0.027; first IFN MS versus long-term IFN MS, P = 0.036) were found. The long-term IFN MS group had higher K/T ratios at 4 and 12 h post-administration (P = 0.015 and 0.009, respectively). The increase of K/T ratio in the first IFN MS group indicate an induction of the enzyme indolamine-2,3-dioxygenase (IDO), as reported earlier in experimental allergic encephalomyelitis. As IDO is participating in both inflammatory and neurodegenerative processes, further knowledge of its involvement in the pathogenesis of MS is of great importance.
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PMID:Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients. 1605 72

Several distinct molecules involved in maternal-conceptus interactions have been discovered in ruminants. Among these are two families of immunoregulatory molecules that represent genes that have undergone evolution to perform a function distinct from that of the ancestral gene. Interferon-tau (IFN-tau) is a product of the trophoblast that retains its antiviral activity and other functions characteristic of interferons but whose primary role is the inhibition of luteolysis. The uterine serpins are progesterone-induced members of the serpin superfamily of serine proteinase inhibitors. The uterine serpin has only a weak antiproteinase activity and, at least in the sheep, appears to function as an inhibitor of lymphocyte proliferation to mediate the immunosuppressive effects of progesterone on uterine immune function. The IFN-tau are not present in mammals that diverged from ancestors of ruminants before 36 million years ago, the approximate origin of IFN-tau, but uterine serpins apparently arose before the divergence of mammals and the proteins are present in at least one nonruminant species, the pig. The clinical value of these molecules can extend beyond use in ruminants. IFN-tau has been used to treat experimental allergic encephalomyelitis in mice and can inhibit human immunodeficiency virus replication. Ovine uterine serpin is also active against murine and human cells but a clinical use has not yet been identified.
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PMID:Pregnancy-associated immunoregulatory molecules discovered in ruminants and their possible relevance to other species. 1612 40

Rabies virus (RV) induces encephalomyelitis in humans and animals. However, the pathogenic mechanism of rabies is not fully understood. To investigate the host responses to RV infection, we examined and compared the pathology, particularly the inflammatory responses, and the gene expression profiles in the brains of mice infected with wild-type (wt) virus silver-haired bat RV (SHBRV) or laboratory-adapted virus B2C, using a mouse genomic array (Affymetrix). Extensive inflammatory responses were observed in animals infected with the attenuated RV, but little or no inflammatory responses were found in mice infected with wt RV. Furthermore, attenuated RV induced the expression of the genes involved in the innate immune and antiviral responses, especially those related to the alpha/beta interferon (IFN-alpha/beta) signaling pathways and inflammatory chemokines. For the IFN-alpha/beta signaling pathways, many of the interferon regulatory genes, such as the signal transduction activation transducers and interferon regulatory factors, as well as the effector genes, for example, 2'-5'-oligoadenylate synthetase and myxovirus proteins, are highly induced in mice infected with attenuated RV. However, many of these genes were not up-regulated in mice infected with wt SHBRV. The data obtained by microarray analysis were confirmed by real-time PCR. Together, these data suggest that attenuated RV activates, while pathogenic RV evades, the host innate immune and antiviral responses.
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PMID:Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. 1616 Jan 83

We have previously characterized a novel tyrosine kinase inhibitor peptide (Tkip) that is a mimetic of suppressor of cytokine signaling 1 (SOCS-1) and inhibits JAK2 phosphorylation of the transcription factor STAT1alpha. We show in this study that Tkip protects mice against experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis. Mice are immunized with myelin basic protein (MBP) for induction of disease. Tkip (63 mug) administered every other day suppressed the development of acute EAE in 75% of New Zealand White (NZW) mice. Furthermore, Tkip completely protected SJL/J mice, which where induced to get the relapsing/remitting form of EAE, against relapses compared with control groups in which >70% of the mice relapsed after primary incidence of disease. Protection of mice by Tkip was similar to that seen with the type I IFN, IFN-tau. Protection of mice correlated with lower MBP Ab titers in Tkip-treated groups as well as suppression of MBP-induced proliferation of splenocytes taken from EAE-afflicted mice. Cessation of Tkip and IFN-tau administration resulted in SJL/J mice relapsing back into disease. Prolonged treatment of mice with Tkip produced no evidence of cellular toxicity or weight loss. Consistent with its JAK2 inhibitory function, Tkip also inhibited the activity of the inflammatory cytokine TNF-alpha, which uses the STAT1alpha transcription factor. The data presented in this study show that Tkip, like the type I IFN, IFN-tau, inhibits both the autoreactive cellular and humoral responses in EAE and ameliorates both the acute and chronic relapsing/remitting forms of EAE.
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PMID:Treatment of mice with the suppressor of cytokine signaling-1 mimetic peptide, tyrosine kinase inhibitor peptide, prevents development of the acute form of experimental allergic encephalomyelitis and induces stable remission in the chronic relapsing/remitting form. 1621 Jun 11

SJL mice exhibit a relapsing-remitting course of experimental autoimmune encephalomyelitis (EAE), whereas C57BL/6 (B6) mice display a more chronic course without complete remissions. Suppressor of cytokine signaling (SOCS)-1 and SOCS-3 are members of a family of inducible intracellular proteins that negatively regulate cytokine signaling in cells of hematopoietic origin and may influence the Th1 to Th2 balance. SOCS-1 and SOCS-3 are induced by cytokines that are known to be up-regulated during EAE, including IFN-gamma (IFN-g) and IL-6, respectively. To test the hypothesis that the level of induction of SOCS-1 and SOCS-3 correlates with the course of EAE, mRNA levels were compared in spinal cords of SJL and B6 mice during discrete stages of disease. SOCS-1 and SOCS-3 were elevated throughout active disease in both strains. At peak EAE, SOCS-1 was higher and SOCS-3 was lower in B6 cords compared with SJL cords. This correlated with greater expression of the Th1 cytokine, IFN-g, and less of the Th2 cytokine, IL-10, in B6 cords relative to SJL cords during onset and peak disease. SOCS-3 inducers in the IL-6 family were expressed differentially between the strains. IL-6 and leukemia inhibitory factor were higher at onset in B6 cords whereas ciliary neurotrophic factor was increased in SJL cords during peak disease. Expression of fibroblast growth factor-2, which may be involved in remyelination, was higher in SJL cords at peak. Comparison of these models suggests that cytokine autoregulatory mechanisms involving SOCS may play a role in determining the course of EAE.
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PMID:Differential expression of suppressors of cytokine signaling-1 and -3 and related cytokines in central nervous system during remitting versus non-remitting forms of experimental autoimmune encephalomyelitis. 1637 62


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