title: Inhibition of the type I immune responses of human monocytes by IFN-α and IFN-β.
abstract: Interleukin-12 (IL-12), IL-23 and interferon-γ (IFN-γ) are pivotal cytokines acting in concert with tumor necrosis factor (TNF) and IL-1β to shape type I immune responses against bacterial pathogens. Recently, several groups reported that type I immunity can be inhibited by IFN-α/β. Here we show the extent of the inhibitory effects of IFN-α and IFN-β on the responsiveness of human monocytes to Toll like receptor-ligands and IFN-γ. Both IFN-α and IFN-β strongly reduced the production of IL-12p40, IL-1β and TNF and the IFN-γ induced CD54 and CD64 expression. High IFN-γ concentrations could not counterbalance the inhibitions and IFN-α still inhibited monocytes 24h after stimulation in vitro as well as in vivo in patients undergoing IFN-α treatment. Next, we explored the mechanism of inhibition. We confirm that IFN-α/β interferes with the IFN-γR1 expression, by studying the kinetics of IFN-γR1 downregulation. However, IFN-γR1 downregulation occurred only after two hours of IFN-α/β stimulation and was transient, which cannot explain the IFN-γ unresponsiveness observed directly and late after IFN-α/β stimulation. Additional experiments indeed indicate that other mechanisms are involved. IFN-α may interfere with IFN-γ-elicited phosphorylation of signal transducer and activator of transcription 1 (STAT1). IFN-α may also activate methyltransferases which in turn reduce, at least partly, the TNF and IL-1β production and CD54 expression. IFN-α also induces the protein inhibitor of activated STAT1 (PIAS1). In conclusion, IFN-α and IFN-β strongly inhibit the IFN-γ responsiveness and the production of type I cytokines of monocytes, probably via various mechanisms. Our findings indicate that IFN-α/β play a significant role in the immunopathogenesis of bacterial infections, for example Mycobacterium tuberculosis infection.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Roelof A
authors.initials: RA
authors.lastname: de Paus
authors.forename: Annelies
authors.initials: A
authors.lastname: van Wengen
authors.forename: Iris
authors.initials: I
authors.lastname: Schmidt
authors.forename: Marten
authors.initials: M
authors.lastname: Visser
authors.forename: Els M E
authors.initials: EM
authors.lastname: Verdegaal
authors.forename: Jaap T
authors.initials: JT
authors.lastname: van Dissel
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
mesh_terms: D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D008024:Ligands; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016898:Interferon-alpha; D053762:Interleukin-12 Subunit p40; D008024:Ligands; C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; D017452:Receptors, IgG; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D025841:Small Ubiquitin-Related Modifier Proteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta; D007371:Interferon-gamma; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases