title: Type I IFNs differentially modulate IL-12p70 production by human dendritic cells depending on the maturation status of the cells and counteract IFN-gamma-mediated signaling.
abstract: Type I IFNs (IFNalpha/beta) are approved for the treatment of a variety of diseases, including the autoimmune disease multiple sclerosis (MS). The proinflammatory cytokines IL-12 and IFN-gamma have been proposed to contribute to the pathogenesis of MS. Since dendritic cells (DCs) are recognized as major producers of IL-12p70 and promote the development of IFN-gamma-producing Th1 cells, we investigated the direct effect of IFNalpha/beta on monocyte-derived DCs at different stages of development. We demonstrate that IFNalpha/beta enhance IL-12p70 production by immature DCs but inhibit IL-12p70 production by mature DCs. Importantly, IFNalpha/beta strongly counteracted the IL-12-enhancing effect of IFN-gamma on DCs irrespective of their maturation status. Exposure of DCs to IFNalpha/beta during maturation does not affect their maturation or cytokine profile upon CD40 ligation. The differential modulatory effect of IFNalpha/beta on the IL-12-producing capacity of DCs and their cross-regulatory effect on IFN-gamma may reduce inflammatory processes and therefore be therapeutically effective in MS.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: H C
authors.initials: HC
authors.lastname: Heystek
authors.forename: B
authors.initials: B
authors.lastname: den Drijver
authors.forename: M L
authors.initials: ML
authors.lastname: Kapsenberg
authors.forename: R A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: E C
authors.initials: EC
authors.lastname: de Jong
mesh_terms: D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D010641:Phenotype; D021122:Protein Subunits / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D007370:Interferon Type I; D008070:Lipopolysaccharides; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma