Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy.
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins are newly identified immunomodulators. In vivo treatment of SJL/J mice with lovastatin reduced the duration and clinical severity of active and passive experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Lovastatin induced the expression of GATA3 and the phosphorylation of STAT6, whereas it inhibited tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT4. Inhibition of the Janus kinase-STAT4 pathway by lovastatin modulated T0 to Th1 differentiation and reduced cytokine (IFN-gamma and TNF-alpha) production, thus inducing Th2 cytokines (IL-4, IL-5, and IL-10). It inhibited T-bet (T box transcription factor) and NF-kappaB in activated T cells and significantly reduced infiltration of CD4- and MHC class II-positive cells to CNS. Further, it stabilized IL-4 production and GATA-3 expression in differentiated Th2 cells, whereas in differentiated Th1 cells it inhibited the expression of T-bet and reduced the production of IFN-gamma. Moreover, lovastatin-exposed macrophage and BV2 (microglia) in allogeneic MLRs induced the production of the anti-inflammatory cytokine IL-10. These observations indicate that the anti-inflammatory effects of lovastatin are mediated via T cells as well as APCs, because it modulates the polarization patterns of naive T cell activation in an APC-independent system. Together, these findings reveal that lovastatin may have possible therapeutic value involving new targets (in both APCs and T cells) for the treatment of multiple sclerosis and other inflammatory diseases.
Nath
Narender
N
Department of Pediatrics, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, 96 Jonathan Lucas Street, Charleston, SC 29425.
Giri
Shailendra
S
Prasad
Ratna
R
Singh
Avtar K
AK
Singh
Inderjit
I
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D050990:GATA3 Transcription Factor; D006131:Growth Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007399:Interphase / Q000187:drug effects / Q000276:immunology; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control; D018991:Myelin Proteolipid Protein / Q000037:antagonists & inhibitors / Q000276:immunology; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D020825:T-Box Domain Proteins; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006131:Growth Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018991:Myelin Proteolipid Protein; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D008148:Lovastatin