title: The role of glycogen synthase kinase 3 in regulating IFN-β-mediated IL-10 production.
abstract: The ability of IFN-β to induce IL-10 production from innate immune cells is important for its anti-inflammatory properties and is believed to contribute to its therapeutic value in treating multiple sclerosis patients. In this study, we identified that IFN-β stimulates IL-10 production by activating the JAK1- and PI3K-signaling pathways. JAK1 activity was required for IFN-β to activate PI3K and Akt1 that resulted in repression of glycogen synthase kinase 3 (GSK3)-β activity. IFN-β-mediated suppression of GSK3-β promoted IL-10, because IL-10 production by IFN-β-stimulated dendritic cells (DC) expressing an active GSK3-β knockin was severely reduced, whereas pharmacological or genetic inhibition of GSK3-β augmented IL-10 production. IFN-β increased the phosphorylated levels of CREB and STAT3 but only CREB levels were affected by PI3K. Also, a knockdown in CREB, but not STAT3, affected the capacity of IFN-β to induce IL-10 from DC. IL-10 production by IFN-β-stimulated DC was shown to suppress IFN-γ and IL-17 production by myelin oligodendrocyte glycoprotein-specific CD4(+) T cells, and this IL-10-dependent anti-inflammatory effect was enhanced by directly targeting GSK3 in DC. These findings highlight how IFN-β induces IL-10 production and the importance that IL-10 plays in its anti-inflammatory properties, as well as identify a therapeutic target that could be used to increase the IL-10-dependent anti-inflammatory properties of IFN-β.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Huizhi
authors.initials: H
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brown
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Garcia
authors.forename: Yunan
authors.initials: Y
authors.lastname: Tang
authors.forename: Manjunatha R
authors.initials: MR
authors.lastname: Benakanakere
authors.forename: Terrance
authors.initials: T
authors.lastname: Greenway
authors.forename: Pascale
authors.initials: P
authors.lastname: Alard
authors.forename: Denis F
authors.initials: DF
authors.lastname: Kinane
authors.forename: Michael
authors.initials: M
authors.lastname: Martin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D055879:Gene Knock-In Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D016899:Interferon-beta / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000502:physiology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; C508609:IL10 protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D016753:Interleukin-10; D016899:Interferon-beta; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3