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)

We previously demonstrated the therapeutic effects of ethinyl estradiol (EE), an orally active estrogen and a component of birth control pills, in encephalitogenic autoimmune encephalomyelitis (EAE). In this study, we report the effectiveness of EE in treating collagen-induced arthritis (CIA) induced with bovine type II collagen (bCII) in DBA/1LacJ mice, a CIA susceptible strain. Both low and high doses of EE notably suppressed clinical and histological signs of CIA in a dose-dependent manner compared to vehicle-treated controls. Oral treatment with EE decreased proliferation and secretion of pro-inflammatory factors, TNF-alpha IFN-gamma, MCP-1 and IL-6 by bCII peptide-specific T cells, production of bCII-specific IgG2a antibodies, and mRNA for cytokines, chemokines and chemokine receptors in joint tissue. This is the first report demonstrating effective treatment of joint inflammation and clinical signs of CIA with orally administered ethinyl estradiol, thus supporting its possible clinical use for treating rheumatoid arthritis in humans.
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PMID:Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-alpha and IL-1beta. 1588 39

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). In the present study we investigated the effects of PPAR-alpha agonists on primary mouse microglia, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO production by cytokine-stimulated microglia in a dose-dependent manner. However, fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and ciprofibrate. In LPS-stimulated microglia, only fenofibrate and WY 14,643 significantly suppressed NO production. Additionally, PPAR-alpha agonists inhibited the secretion of the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, the RXR agonist 9-cis retinoic acid (9-cis RA) inhibited NO production by LPS-stimulated microglia. Furthermore, a combination of 9-cis RA and the PPAR-alpha agonist fenofibrate cooperatively inhibited NO production by these cells. A combination of these agonists also selectively inhibited the expression of proinflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 by LPS-stimulated microglia. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might have benefit as a therapy in MS, where activated microglia are believed to contribute to disease pathology.
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PMID:Agonists for the peroxisome proliferator-activated receptor-alpha and the retinoid X receptor inhibit inflammatory responses of microglia. 1596 40

Retinoic acid (RA) regulates a wide range of biologic process, including inflammation. Previously, RA was shown to inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The current study investigated the effects of 9-cis-RA on primary mouse microglia and astrocytes, two cell types implicated in the pathology of MS and EAE. The studies demonstrated that 9-cis-RA inhibited the production of nitric oxide (NO) as well as the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-12 p40 by LPS-stimulated microglia. However, this retinoid had no effect on IL-6 secretion and increased MCP-1 production by LPS-stimulated microglia. In LPS-stimulated astrocytes, 9-cis-RA inhibited NO and TNF-alpha production but had not effect on IL-1beta, IL-6 and MCP-1 secretion. These results suggest that RA modulates EAE, at least in part, by suppressing the production of NO and specific inflammatory cytokines from activated glia and suggests that RA might be effective in the treatment of MS.
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PMID:9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytes. 1630 84

We examined the role of tumor necrosis factor receptor 1 (TNFR1) in inflammation initiated by the adoptive transfer of central nervous system (CNS)-specific Th1 cells in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. This adoptive transfer paradigm eliminates the confounding effects of bacterial adjuvants in the analysis of inflammation. We found that although T cells could reach the meninges and perivascular space in the absence of TNFR1, recruitment of other inflammatory cells from the blood was dramatically reduced. The reduction in the recruitment of CD11b(hi) cells correlated with a dramatic reduction in the production of the chemokines CCL2 (MCP-1) and CXLC2 (MIP-2) in TNFR1-deficient hosts. Bone marrow chimera experiments demonstrated that TNF can be effectively supplied by either the hematopoietic system or the CNS, but the essential TNFR1-responsive cells reside in the CNS. Previous work has demonstrated that microglia produce CCL2, and here we demonstrate that astrocytes and endothelial cells produced CXCL2 in the early stages of inflammation. Therefore, productive inflammation results from a conversation, or mutually responding signals, between the initiating T cells and cells in the parenchyma of the spinal cord.
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PMID:A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. 1656 95

Theiler's murine encephalomyelitis virus (TMEV) infection in the central nervous system (CNS) induces a demyelinating disease similar to human multiple sclerosis. TMEV infection results in activation of various chemokine and cytokine genes that are important in the initiation of an inflammatory response. We have previously shown that the production of these chemokines and cytokines in astrocytes is induced via the NF-kappaB pathway following TMEV and Coxsackie virus infection. In this study, we investigated whether the NF-kappaB-dependent inflammatory responses after TMEV infection is triggered through TLR3 and/or TLR7. The activation of NF-kappaB or IRF/ISRE, as well as the production of both MCP-1/CCL2 and IL-8/CXCL8, was observed in only TLR3-transfected HEK 293 cells, but not in TLR7-tranfected cells. The potential involvement of TLR3 in mouse embryonic fibroblasts and primary astrocytes was further investigated following transfection with wildtype or dominant negative form of TLRs and MyD88, as well as astrocytes from TLR3- and MyD88-deficient mice. Similarly, the activation of transcription factors and chemokine genes is induced in these mouse cells through primarily TLR3 signaling pathway, but not TLR7 or other MyD88-mediated pathways following TMEV infection. However, the TLR3-mediated cellular activation does not appear to affect the level of viral replication in astrocytes. These results strongly suggest that TLR3-signaling by TMEV alone is sufficient to induce the initial inflammatory cytokine responses that could be very important for the outcome of virus-induced encephalitis and/or demyelinating diseases, such as multiple sclerosis.
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PMID:Induction of chemokine and cytokine genes in astrocytes following infection with Theiler's murine encephalomyelitis virus is mediated by the Toll-like receptor 3. 1658 93

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In the present study, we investigated the effects of PPAR-alpha agonists on primary mouse astrocytes, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists fenofibrate, and WY 14643 inhibited NO production by LPS-stimulated astrocytes in a dose-dependent manner. Additionally, PPAR-alpha agonists inhibited the secretion of the pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 by LPS-stimulated astrocytes. Fenofibrate inhibited NF-kappaB DNA binding activity, suggesting a mechanism by which PPAR-alpha agonists may regulate the expression of genes encoding these pro-inflammatory molecules. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, a combination of 9-cis RA and the PPAR-alpha agonists fenofibrate or gemfibrozil cooperatively inhibited NO, TNF-alpha, IL-1beta, IL-6, and MCP-1 production by these cells. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might be effective in the treatment of MS, where activated astrocytes are believed to contribute to disease pathology.
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PMID:Peroxisome proliferator-activated receptor-alpha and retinoid X receptor agonists inhibit inflammatory responses of astrocytes. 1676 43

Dendritic cell (DC) maturation can occur by different types of stimuli. Previously, we described that murine DC matured with tumor necrosis factor (TNF) up-regulate surface MHC and costimulatory molecules but lack cytokine release, and therefore termed them semi-mature DC. These TNF/DC-induced tolerance after intravenous (i.v.) injection in a model of experimental autoimmune encephalomyelitis (EAE). Here, we show that TNF/DC are not terminally differentiated but can still respond to the microbial stimulus lipopolysaccharide. Subcutaneously injected TNF/DC induce an unpolarized T(H)1/T(H)2 response and are not protective in the experimental autoimmune encephalomyelitis model. Although TNF/DC home to the draining lymph node, they remain negative for intracellular cytokine stainings. However, the nonmigrating, endogenous DC started to produce interleukin (IL)-12p40, TNF and little IL-6, IL-10, and MCP-1 in a bystander fashion. Together, DC matured with the inflammatory stimulus TNF remains responsive to further signals in vitro and in vivo. These signals can be provided by pathogens or the subcutaneous injection route, which can convert them from tolerogenic to immunogenic DC. These findings are important for selecting the appropriate injection route of human DC for tumor immunotherapy.
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PMID:Dendritic cells matured with TNF can be further activated in vitro and after subcutaneous injection in vivo which converts their tolerogenicity into immunogenicity. 1679 36

Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human demyelinating disorder multiple sclerosis (MS). The immune cytokine interferon-gamma (IFN-gamma) is believed to participate in disease pathogenesis in both EAE and MS. In the present study, we examined the significance of IFN-gamma-oligodendrocyte interactions in the course of EAE. For the purpose of our study, we used the previously described [proteolipid protein/suppressor of cytokine signaling 1 (PLP/SOCS1)] transgenic mouse line that displays suppressed oligodendrocyte responsiveness to IFN-gamma. PLP/SOCS1 mice developed EAE with an accelerated onset associated with enhanced early inflammation and markedly increased oligodendrocyte apoptosis. Moreover, we found that IFN-gamma pretreatment of mature oligodendrocytes in vitro had a protective effect against oxidative stress and the inhibition of proteasome activity and resulted in upregulation in expression of a number of chemokines, including CXCL10 (IP10), CCL2 (MCP-1), CCL3 (MCP-1alpha), and CCL5 (RANTES). These results suggest that IFN-gamma-oligodendrocyte interactions are of significance to the clinical and pathological aspects of EAE. In addition, the present study suggests that oligodendrocytes are not simply targets of inflammatory injury but active participants of the neuroimmune network operating during the course of EAE.
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PMID:Interferon-gamma-oligodendrocyte interactions in the regulation of experimental autoimmune encephalomyelitis. 1731 97

Pro-inflammatory cytokines/chemokines are implemented in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model with clinical and pathological similarities to multiple sclerosis. We have previously shown that over-expression of glia maturation factor (GMF) in glial cells cause excessive production and secretion of pro-inflammatory cytokines/chemokines sufficient to destroy the myelin-forming oligodendroglial cell in vitro. In this present investigation, we evaluate the expression of pro-inflammatory mediators in the central nervous system (CNS) of GMF+/+ (wild type) mice and GMF-/- (GMF-knockout) mice at the peak of EAE induced by immunization with MOG 35-55 peptide. GMF+/+ (Wt) mice developed severe EAE with a maximal mean clinical score of 3.6+/-0.5 by day 16 post-immunization, whereas GMF-KO mice showed significantly delayed EAE with an average onset on day 26 pi with reduced mean clinical score of 1.3+/-0.3. Three of fifteen Wt mice as compared to none of GMF-KO mice died of EAE. Encephalitogenic cells from Wt mice transferred to recipient GMF-KO mice caused very mild and with low incidence of EAE. We determined the differences in the expression of cytokines, IFN-gamma, TNF-alpha, IL-1 beta, IL-6, IL-4, IL-10, and chemokines, MIP-1, MIP-2, IP-10, MCP-1, GM-CSF mRNA by quantitative real-time RT-PCR in brain and spinal cord. Our results demonstrate significantly low levels of pro-inflammatory cytokines/chemokines in the CNS of GMF-KO mice and increased expression in Wt mice with EAE. Our data suggest that GMF play a critical role in CNS inflammation.
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PMID:Diminished cytokine and chemokine expression in the central nervous system of GMF-deficient mice with experimental autoimmune encephalomyelitis. 1731 72

The therapeutic value of an antirheumatic alkaloid, sinomenine (SIN), was investigated in the acute experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). SIN is a bioactive alkaloid derived from the Chinese medicinal plant, Sinomenium acutum REHDER & E. H. WILSON (Family Menispermaceae). Chinese doctors have utilized this plant to treat rheumatic and arthritic diseases for over one thousand years. Experiments in which EAE-induced Lewis rats exhibit an acute monophasic episode of disease demonstrated that SIN is effective in preventing clinical signs of disease. The therapeutic effect on disease activity was observed at preonset administration times and at various doses tested. Consistent with disease activity in vivo, SIN-treated animals have reduced cellular infiltration within the spinal cord along with decreased TNF-alpha and IFN-gamma expression levels. SIN can significantly inhibit proliferation response of splenocytes induced by MBP(68-82). TNF-alpha and IFN-gamma, secreted by splenocytes induced by MBP(68-82) are inhibited by SIN by dose-dependence manner. The mRNA levels of CC chemokines, RANTES, MIP-1alpha and MCP-1, are inhibited in SIN-treated EAE rats. The data in this proof of concept study support the premise that SIN may be a promising new therapeutic intervention in MS.
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PMID:Sinomenine, an antirheumatic alkaloid, ameliorates clinical signs of disease in the Lewis rat model of acute experimental autoimmune encephalolmyelitis. 1766


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