Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low-dose estrogen (E2) treatment significantly inhibits the clinical signs and histopathological lesions of experimental autoimmune encephalomyelitis (EAE), and is being used in clinical trials to treat multiple sclerosis. To assess the role of intracytoplasmic estrogen receptors in mediating suppression of EAE, we studied mice with disrupted estrogen receptor-alpha (Esr1) and -beta (Esr2) genes. We demonstrate that the protective effect of E2 is abrogated in B6.129-Esr1(tm1Unc) mice (Esr1-/-) but not in B6.129-Esr2(tm1Unc) mice (Esr2-/-). The loss of E2-mediated protection from EAE in Esr1-/- mice immunized with the encephalitogenic MOG-35-55 peptide was manifested phenotypically by the development of severe acute clinical signs and histopathological lesions even in the presence of moderately high serum E2 levels. This is in contrast to C57BL/6 wild-type (WT) mice and Esr2-/- mice in which E2 treatment resulted in comparable serum levels and markedly suppressed clinical signs of EAE and abolished inflammatory lesions in the CNS. This pattern showing a lack of E2-dependent inhibition of EAE in Esr1-/- mice was mirrored by an enhanced rather than a reduced secretion of TNF-alpha, IFN-gamma, and interleukin (IL)-6 in MOG-specific splenocytes and a lack of inhibition of message for inflammatory cytokines, chemokines and chemokine receptors in CNS tissue. These results indicate that the immunomodulatory effects of E2 in EAE are dependent on Esr1 and not Esr2 signaling.
 ...
PMID:The protective effect of 17beta-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-alpha. 1450 66

Estrogens and estrogen-receptor signaling function in establishing and regulating the female immune system and it is becoming increasingly evident that they may play a similar role in males. We report that B10.PL/SnJ male mice with a disrupted estrogen receptor-1 (alpha) gene (Esr1(-/-)) develop less severe clinical experimental allergic encephalomyelitis (EAE) compared to either Esr1(+/-) or wild-type (Esr1(+/+)) controls when immunized with myelin basic protein peptide Ac1-11 (MBP(Ac1-11)). In contrast, the disease course in B10.PL/SnJ male mice with a disrupted estrogen receptor-2 (beta) gene (Esr2(-/-)) does not differ from that of wild-type (Esr2(+/+)) mice. However, Esr2(+/-) mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males. No significant differences in central nervous system histopathology or MBP(Ac1-11)-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype. An analysis of cytokine/chemokine secretion by MBP(Ac1-11)-specific T cells revealed unique Esr1 and Esr2 genotype-dependent regulation. Interferon-gamma secretion was found to be negatively regulated by Esr1 whereas interleukin-6 and tumor necrosis factor-alpha secretion exhibited classical Esr2 gene dose responses. Interestingly, MCP-1 displayed distinctively unique patterns of genotype-dependent regulation by Esr1 and Esr2. The contribution of the hematopoietic and nonhematopoietic cellular compartments associated with the heterotic effect at Esr2 in regulating the severity of clinical EAE was identified using reciprocal hematopoietic radiation bone marrow chimeras generated between male wild-type and Esr2(+/-) mice. Wild-type --> Esr2(+/-) mice exhibited EAE equivalent in severity to that seen in Esr2(+/-) --> Esr2(+/-) control constructs; both of which were more severe than the clinical signs observed in Esr2(+/-) --> wild-type and wild-type --> wild-type mice. These results indicate that the heterotic effect at Esr2 is a function of the nonhematopoietic compartment.
 ...
PMID:Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice. 1516 28

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERalpha and ERbeta. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17beta-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERalpha-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERbeta-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERbeta agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERalpha-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.
 ...
PMID:Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands. 1584 17

Treatment with either estradiol or an estrogen receptor (ER)alpha ligand has been shown to be both antiinflammatory and neuroprotective in a variety of neurological disease models, but whether neuroprotective effects could be observed in the absence of an antiinflammatory effect has remained unknown. Here, we have contrasted effects of treatment with an ERalpha vs. an ERbeta ligand in experimental autoimmune encephalomyelitis, the multiple sclerosis model with a known pathogenic role for both inflammation and neurodegeneration. Clinically, ERalpha ligand treatment abrogated disease at the onset and throughout the disease course. In contrast, ERbeta ligand treatment had no effect at disease onset but promoted recovery during the chronic phase of the disease. ERalpha ligand treatment was antiinflammatory in the systemic immune system, whereas ERbeta ligand treatment was not. Also, ERalpha ligand treatment reduced CNS inflammation, whereas ERbeta ligand treatment did not. Interestingly, treatment with either the ERalpha or the ERbeta ligand was neuroprotective, as evidenced by reduced demyelination and preservation of axon numbers in white matter, as well as decreased neuronal abnormalities in gray matter. Thus, by using the ERbeta selective ligand, we have dissociated the antiinflammatory effect from the neuroprotective effect of estrogen treatment and have shown that neuroprotective effects of estrogen treatment do not necessarily depend on antiinflammatory properties. Together, these findings suggest that ERbeta ligand treatment should be explored as a potential neuroprotective strategy in multiple sclerosis and other neurodegenerative diseases, particularly because estrogen-related toxicities such as breast and uterine cancer are mediated through ERalpha.
 ...
PMID:Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. 1778 21

Resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound found in plant products, including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties. Using an animal model of multiple sclerosis (MS), we investigated the use of resveratrol for the treatment of autoimmune diseases. We observed that resveratrol treatment decreased the clinical symptoms and inflammatory responses in experimental allergic encephalomyelitis (EAE)-induced mice. Furthermore, we observed significant apoptosis in inflammatory cells in spinal cord of EAE-induced mice treated with resveratrol compared with the control mice. Resveratrol administration also led to significant down-regulation of certain cytokines and chemokines in EAE-induced mice including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-9, IL-12, IL-17, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), and Eotaxin. In vitro studies on the mechanism of action revealed that resveratrol triggered high levels of apoptosis in activated T cells and to a lesser extent in unactivated T cells. Moreover, resveratrol-induced apoptosis was mediated through activation of aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) and correlated with up-regulation of AhR, Fas, and FasL expression. In addition, resveratrol-induced apoptosis in primary T cells correlated with cleavage of caspase-8, caspase-9, caspase-3, poly(ADP-ribose) polymerase, and release of cytochrome c. Data from the present study demonstrate, for the first time, the ability of resveratrol to trigger apoptosis in activated T cells and its potential use in the treatment of inflammatory and autoimmune diseases including, MS.
 ...
PMID:Resveratrol (trans-3,5,4'-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. 1787 69

Steroidal estrogens can regulate inflammatory immune responses and may be involved in the suppression of multiple sclerosis (MS) during pregnancy. However, the risks and side effects associated with steroidal estrogens may limit their usefulness for long-term MS therapy. Selective estrogen receptor modulators (SERMs) could provide an alternative therapeutic strategy, because they behave as estrogen agonists in some tissues, but are either inert or behave like estrogen antagonists in other tissues. In this study, we investigated the ability of two commercially available SERMs (tamoxifen and raloxifene) to regulate myelin specific immunity and experimental autoimmune encephalomyelitis (EAE) in mice. Both tamoxifen and raloxifene suppressed myelin antigen specific T-cell proliferation. However, tamoxifen was more effective in this regard. Tamoxifen treatment reduced the induction of major histocompatibility complex II by lipopolysaccharide stimulated dendritic cells and decreased their ability to activate myelin specific T-cells. At lower doses, tamoxifen was found to increase the levels of Th2 transcription factors and induce a Th2 bias in cultures of myelin-specific splenocytes. EAE symptoms and the degree of demyelination were less severe in mice treated with tamoxifen than in control mice. These findings support the notion that tamoxifen or related SERMs are potential agents that could be used in the treatment of inflammatory autoimmune disorders that affect the central nervous system.
 ...
PMID:Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis. 1903 37

Although estrogens exert a pronounced protective effect on multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), their therapeutic application has been limited by undesirable side effects thought to be mediated primarily through estradiol binding to intracellular estrogen receptor alpha. In this study, we found that signaling through the putative membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), was sufficient to mediate protection against EAE, which was significantly impaired in GPR30 gene-deficient mice. Treatment with G-1, an agonist that selectively activates GPR30 without engagement of the intracellular estrogen receptors, retained the ability of estradiol to protect against clinical and histological EAE without estradiol-associated side effects, deviated cytokine profiles, and enhanced suppressive activity of CD4(+)Foxp3(+) T regulatory cells through a GPR30- and programmed death 1-dependent mechanism. This study is the first to evaluate the protective effect of GPR30 activation on EAE, and provides a strong foundation for the clinical application of GPR30 agonists such as G-1 in multiple sclerosis.
 ...
PMID:Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1. 1923 28

Demyelination and neurodegeneration is a major contributor in the progression of disability in multiple sclerosis (MS). Thus, the development of therapies that are neuroprotective has elicited considerable interests. Estrogens and estrogen receptor (ER) ligand treatments are promising treatments to prevent MS-induced neurodegeneration and a multicenter phase II clinical trial of estriol as a beneficial therapy in MS is underway. Here, we discuss studies performed in our laboratory that examined the effects of ER ligands in the inflammatory/demyelinating disorder experimental autoimmune encephalomyelitis (EAE), a model of MS. Administration of estriol or 17beta-estradiol reduced clinical severity and this clinical disease improvement was associated with favorable changes in cytokine production. There was a significant decrease of neuronal pathology in gray matter along with myelin and axon preservation in white matter of spinal cords of mice with EAE. In subsequent experiments, we contrasted the results of ERalpha versus ERbeta ligand treatment. While ERalpha ligand treatment was anti-inflammatory, ERbeta ligand treatment was not. ERbeta ligand treatment nevertheless reduced demyelination and preserved axon numbers in white matter and prevented neuronal abnormalities in gray matter. Clinically, ERalpha ligand treatment abrogated the disease at the onset, while ERbeta ligand treatment had no effect at disease onset, but promoted recovery. Thus, unlike ERalpha ligand treatment, ERbeta ligand treatment was protective at the level of the target organ, independent of anti-inflammatory effects in the peripheral immune system. ERbeta ligand treatment should be considered as a potential neuroprotective agent for MS and other neurodegenerative diseases, particularly since breast and uterine cancer are mediated through ERalpha.
 ...
PMID:Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice. 1944 88

Matrix metalloproteinases (MMPs) have a crucial function in migration of inflammatory cells into the central nervous system (CNS). Levels of MMP-9 are elevated in multiple sclerosis (MS) and predict the occurrence of new active lesions on magnetic resonance imaging (MRI). This translational study aims to determine whether in vivo treatment with the pregnancy hormone estriol affects MMP-9 levels from immune cells in patients with MS and mice with experimental autoimmune encephalomyelitis (EAE). Peripheral blood mononuclear cells (PBMCs) collected from three female MS patients treated with estriol and splenocytes from EAE mice treated with estriol, estrogen receptor (ER) alpha ligand, ERbeta ligand or vehicle were stimulated ex vivo and analyzed for levels of MMP-9. Markers of CNS infiltration were assessed using MRI in patients and immunohistochemistry in mice. Supernatants from PBMCs obtained during estriol treatment in female MS patients showed significantly decreased MMP-9 compared with pretreatment. Decreases in MMP-9 coincided with a decrease in enhancing lesion volume on MRI. Estriol treatment of mice with EAE reduced MMP-9 in supernatants from autoantigen-stimulated splenocytes, coinciding with decreased CNS infiltration by T cells and monocytes. Experiments with selective ER ligands showed that this effect was mediated through ERalpha. In conclusion, estriol acting through ERalpha to reduce MMP-9 from immune cells is one mechanism potentially underlying the estriol-mediated reduction in enhancing lesions in MS and inflammatory lesions in EAE.
 ...
PMID:Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha). 1966 39

The disease activity of multiple sclerosis (MS) is known to be ameliorated during pregnancy, and pregnancy is also found to be protective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Estrogen levels increase during pregnancy and basic researches have shown that estrogens have immunomodulatory effects on immune cells. The importance of estrogen in pathogenic autoimmune diseases has also been demonstrated in EAE by altering hormone levels. Mice treated with estrogen experienced significantly decreased EAE severity and delayed onset of disease as a result of neuroprotective and anti-inflammatory effects. Brain atrophy has been detected at the early stages of MS by using MRI; thus, as a neuroprotective agent, estrogen might be effective against brain atrophy. Estrogen's effects are primarily mediated by the nuclear estrogen receptor (ER), and recent studies have shown the presence of nuclear ERs on the cells involved in the immune response. There have been some reports on genetic polymorphisms of ERs in MS. In this review paper, we discuss increasing evidence that points to a link between estrogen and MS. We also analyze the therapeutic potential of estrogens in MS and review current genetic studies on ER.
 ...
PMID:Estrogens as potential therapeutic agents in multiple sclerosis. 2002 42


1 2 3 4 Next >>