title: Regulation of Th1 cells and experimental autoimmune encephalomyelitis by glycogen synthase kinase-3.
abstract: Experimental autoimmune encephalomyelitis (EAE) is a rodent model of multiple sclerosis (MS), a debilitating autoimmune disease of the CNS, for which only limited therapeutic interventions are available. Because MS is mediated in part by autoreactive T cells, particularly Th17 and Th1 cells, in the current study, we tested whether inhibitors of glycogen synthase kinase-3 (GSK3), previously reported to reduce Th17 cell generation, also alter Th1 cell production or alleviate EAE. GSK3 inhibitors were found to impede the production of Th1 cells by reducing STAT1 activation. Molecularly reducing the expression of either of the two GSK3 isoforms demonstrated that Th17 cell production was sensitive to reduced levels of GSK3β and Th1 cell production was inhibited in GSK3α-deficient cells. Administration of the selective GSK3 inhibitors TDZD-8, VP2.51, VP0.7, or L803-mts significantly reduced the clinical symptoms of myelin oligodendrocyte glycoprotein35-55-induced EAE in mice, nearly eliminating the chronic progressive phase, and reduced the number of Th17 and Th1 cells in the spinal cord. Administration of TDZD-8 or L803-mts after the initial disease episode alleviated clinical symptoms in a relapsing-remitting model of proteolipid protein139-151-induced EAE. Furthermore, deletion of GSK3β specifically in T cells was sufficient to alleviate myelin oligodendrocyte glycoprotein35-55-induced EAE. These results demonstrate the isoform-selective effects of GSK3 on T cell generation and the therapeutic effects of GSK3 inhibitors in EAE, as well as showing that GSK3 inhibition in T cells is sufficient to reduce the severity of EAE, suggesting that GSK3 may be a feasible target for developing new therapeutic interventions for MS.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. ebeurel@med.miami.edu
authors.forename: Eléonore
authors.initials: E
authors.lastname: Beurel
authors.forename: Oksana
authors.initials: O
authors.lastname: Kaidanovich-Beilin
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Yeh
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Michalek
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Harrington
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis; D063308:Myelin-Oligodendrocyte Glycoprotein; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments; D020033:Protein Isoforms / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D063308:Myelin-Oligodendrocyte Glycoprotein; C509073:N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline; D009842:Oligopeptides; D010446:Peptide Fragments; D020033:Protein Isoforms; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D013830:Thiadiazoles; C445081:myelin oligodendrocyte glycoprotein (35-55); D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha