title: Stat4 isoforms differentially regulate inflammation and demyelination in experimental allergic encephalomyelitis.
abstract: Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model of multiple sclerosis. Signal transducer and activator of transcription 4 (Stat4) is a transcription factor activated by IL-12 and IL-23, two cytokines known to play important roles in the pathogenesis of EAE by inducing T cells to secrete IFN-gamma and IL-17, respectively. We and others have previously shown that therapeutic intervention or targeted disruption of Stat4 was effective in ameliorating EAE. Recently, a splice variant of Stat4 termed Stat4beta has been characterized that lacks 44 amino acids at the C terminus of the full-length Stat4alpha. In this study we examined whether T cells expressing either isoform could affect the pathogenesis of EAE. We found that transgenic mice expressing Stat4beta on a Stat4-deficient background develop an exacerbated EAE compared with wild-type mice following immunization with myelin oligodendrocyte glycoprotein peptide 35-55, while Stat4alpha transgenic mice have greatly attenuated disease. The differential development of EAE in transgenic mice correlates with increased IFN-gamma and IL-17 in Stat4beta-expressing cells in situ, contrasting increased IL-10 production by Stat4alpha-expressing cells. This study demonstrates that Stat4 isoforms differentially regulate inflammatory cytokines in association with distinct effects on the onset and severity of EAE.
authors.affiliation: Neuroscience Research Laboratory, Methodist Research Institute, Indianapolis, IN 46202, USA.
authors.forename: Caiqing
authors.initials: C
authors.lastname: Mo
authors.forename: Wanida
authors.initials: W
authors.lastname: Chearwae
authors.forename: John T
authors.initials: JT
authors.lastname: O'Malley
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Adams
authors.forename: Saravanan
authors.initials: S
authors.lastname: Kanakasabai
authors.forename: Crystal C
authors.initials: CC
authors.lastname: Walline
authors.forename: Gretta L
authors.initials: GL
authors.lastname: Stritesky
authors.forename: Seth R
authors.initials: SR
authors.lastname: Good
authors.forename: Narayanan B
authors.initials: NB
authors.lastname: Perumal
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.forename: John J
authors.initials: JJ
authors.lastname: Bright
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006023:Glycoproteins / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000633:toxicity; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000276:immunology*; D017384:Sequence Deletion / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D006023:Glycoproteins; D020381:Interleukin-17; D053759:Interleukin-23; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D020033:Protein Isoforms; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma