title: Differential effects of IFN-β on IL-12, IL-23, and IL-10 expression in TLR-stimulated dendritic cells.
abstract: MS is an autoimmune disease characterized by immune cell infiltration in the CNS, leading to cumulative disability. IFN-β, used clinically in RR-MS reduces lesion formation and rates of relapse. Although the molecular mechanisms are not entirely elucidated, myeloid cells appear to be a major target for the therapeutic effects of IFN-β. DCs have a critical role in experimental models of MS through their effect on encephalitogenic Th1/Th17 cell differentiation and expansion. Here we focused on the effects of IFN-β on DC expression of cytokines involved in the control of Th1/Th17 differentiation and expansion. Administration of IFN-β to mice immunized with MOG35-55 inhibited IL-12 and IL-23 expression in splenic DC and reduced in vivo differentiation of Th1/Th17 cells. IFN-β affected cytokine expression in TLR-stimulated DC in a similar manner in vitro, inhibiting IL-12 and IL-23 and stimulating IL-10 at both mRNA and protein levels, by signaling through IFNAR. We investigated the role of the signaling molecules STAT1/STAT2, IRF-1 and IRF-7, and of the PI3K→GSK3 pathway. IFN-β inhibition of the IL-12 subunits p40 and p35 was mediated through STAT1/STAT2, whereas inhibition of IL-23 was STAT1 dependent, and the stimulatory effect on IL-10 expression was mediated through STAT2. IFN-β induces IRF-7 and, to a lesser degree, IRF-1. However, neither IRF mediated the effects of IFN-β on IL-12, IL-23, or IL-10. We found that the PI3K pathway mediated IL-12 inhibition but did not interfere with the inhibition of IL-23 or stimulation of IL-10.
authors.affiliation: *Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, USA; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
authors.affiliation: *Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, USA; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Kong
authors.affiliation: *Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, USA; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Hooper
authors.affiliation: *Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, USA; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Emig
authors.affiliation: *Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, USA; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Rahbari
authors.affiliation: *Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, USA; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ping-Chang
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: *Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, USA; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Scofield
authors.affiliation: *Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, USA; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA dganea@temple.edu.
authors.forename: Doina
authors.initials: D
authors.lastname: Ganea
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; C508859:Il12a protein, mouse; D050856:Interferon Regulatory Factor-1; D050839:Interferon Regulatory Factor-7; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; C494258:Irf1 protein, mouse; C494235:Irf7 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D051193:Toll-Like Receptors; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10; D016899:Interferon-beta; D019869:Phosphatidylinositol 3-Kinases
keywords: IRF1/IRF7; PI3K/GSK3; STAT1/STAT2; Type I interferons; cytokines