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)

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are approved for cholesterol reduction, may also be beneficial in the treatment of inflammatory diseases. Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4(+) Th1-mediated central nervous system (CNS) demyelinating disease model of multiple sclerosis. Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-beta. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha) was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility complex (MHC) class II expression. Treatment of microglia inhibited IFN-gamma-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has pleiotropic immunomodulatory effects involving both APC and T-cell compartments. Statins may be beneficial for multiple sclerosis and other Th1-mediated autoimmune diseases.
 ...
PMID:The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. 1242 6

Statins, 3-hydroxy-3 methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors, are approved for cholesterol reduction and are commonly used to treat atherosclerosis and coronary disease. Statins may also be potent immunomodulatory agents and be beneficial in the treatment of autoimmune diseases. Statins have already been used to reduce the rejection of human heart transplants by the immune system, and there have been reports of a protective effect of injected statins in models of brain autoimmunity similar to experimental autoimmune encephalomyelitis. In vitro studies in multiple sclerosis(MS) revealed that statins reduced the expression of activation-induced adhesion molecules on T cells, modified Th1/Th2 cytokine balance, reduced matrix metalloproteinase(MMP)-9, and downregulated chemokine receptors on both B and T cells. Thus statins are effective immunomodulators in vitro that merit evaluation as treatment for MS. In vivo studies using three different animal models of MS revealed that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin has been shown to have pleiotropic immunomodulatory effects involving both antigen presenting cells and T cell compartment. Thus, statins may be beneficial for MS, and clinical trials of the effects of statins on MS are now in progress, hopefully in a favorable way.
 ...
PMID:[Effects of atorvastatin in multiple sclerosis]. 1296 38

The effect of Atorvastatin on transcriptional activity in murine experimental autoimmune encephalomyelitis (EAE) induced by PLP peptide 139-151 was analyzed by DNA microarray technique in lymph nodes and spinal cord at onset (10 days), height (20 days) and first remission (30 days) of disease. Fourteen genes were selectively influenced by Atorvastatin in EAE mice. They are mainly related to immune cell functions and regulation of cell-to-cell interaction. Interestingly, seven genes were also differentially regulated in CFA-injected control mice. But qualitative and quantitative differences to EAE mice argue for a dependency of statin effects on the activation status of target cells. Differential regulation of the newly detected candidate genes of statin effects COX-1 and HSP-105 and the previously known statin-responsive genes ICAM-1 and CD86 was confirmed by Western blot and immunohistochemistry. Flow cytometric analysis of lymph node cells revealed that the effect of Atorvastatin treatment in non-immunized healthy animals resembled the effect of immunization with PLP peptide regarding changes of T helper cells, activated B cells and macrophages. In EAE mice, these effects were partially reversed by Atorvastatin treatment. Monitoring of expression of the newly identified candidate genes and patterns of lymphocyte subpopulations might predict the responsiveness of multiple sclerosis patients to statin treatment.
 ...
PMID:3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor Atorvastatin mediated effects depend on the activation status of target cells in PLP-EAE. 1708 13

Atorvastatin and simvastatin (members of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor family) are widely prescribed as cholesterol-lowering agents. As they have been shown to exhibit potent immunomodulatory effects, they may become a future treatment option for autoimmune disease in general and multiple sclerosis (MS) in particular. Several recent reports have demonstrated that statins prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. An open-label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favorable safety profile. The results of a large multicenter, placebo-controlled clinical trial assessing atorvastatin in patients with clinically isolated syndrome (a disease that predisposes to development MS) are expected soon. However, prospective placebo-controlled trials of atorvastatin or simvastatin in definite MS are difficult to perform due to ethical and financial objections. In this review, we discuss the backgrounds, mechanisms of action and future perspectives of atorvastatin and simvastatin as putative future treatment options in MS.
 ...
PMID:Evaluation of atorvastatin and simvastatin for treatment of multiple sclerosis. 1749 4

Oral atorvastatin has prevented or reversed paralysis in the multiple sclerosis (MS) model experimental autoimmune encephalomyelitis (EAE), and reduced development of new MS lesions in clinical trials. Besides inhibiting development of encephalitogenic T cells, atorvastatin treatment of EAE has been associated with an induction of anti-inflammatory myelin-reactive T-helper type (Th)-2 cells. To investigate the clinical significance of atorvastatin-mediated Th2 differentiation, we first evaluated atorvastatin treatment in interleukin (IL)-4 green fluorescent protein-enhanced transcript (4-GET) reporter mice. Atorvastatin treatment failed to induce IL-4-producing Th2 cells in vivo; however, when T cells from atorvastatin-treated 4-GET mice were reactivated in vitro, T cells preferentially differentiated into Th2 cells, while antigen-specific T-cell proliferation and secretion of proinflammatory cytokines (interferon gamma, IL-17, tumor necrosis factor and IL-12) were reduced. Oral atorvastatin also prevented or reversed EAE in signal transducer and activator of transcription 6-deficient (STAT6-/-) mice, which cannot generate IL-4-producing Th2 cells. Further, atorvastatin treatment did not induce or expand Foxp3+ regulatory T cells in either wild-type or STAT6-/- mice. In vivo proliferation of T cells, as measured by incorporation of bromodeoxyuridine, was inhibited in atorvastatin-treated wild-type and STAT6-/- mice. These data imply that atorvastatin ameliorates central nervous system autoimmune disease primarily by inhibiting proliferation of proinflammatory encephalitogenic T cells, and not simply through induction of anti-inflammatory Th2 cells. This cytostatic effect may be a relevant mechanism of action when considering use of statins in MS and other inflammatory conditions.
...
PMID:Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. 2449 70