title: TLR4 ligands induce IFN-alpha production by mouse conventional dendritic cells and human monocytes after IFN-beta priming.
abstract: Exacerbation of disease in systemic lupus erythematosus (SLE) is associated with bacterial infection. In conventional dendritic cells (cDCs), the TLR4 ligand bacterial LPS induces IFN-beta gene expression but does not induce IFN-alpha. We hypothesized that when cDCs are primed by cytokines, as may frequently be the case in SLE, LPS would then induce the production of IFN-alpha, a cytokine believed to be important in lupus pathogenesis. In this study we show that mouse cDCs and human monocytes produce abundant IFN-alpha following TLR4 engagement whether the cells have been pretreated either with IFN-beta or with a supernatant from DCs activated by RNA-containing immune complexes from lupus patients. This TLR4-induced IFN-alpha induction is mediated by both an initial TRIF-dependent pathway and a subsequent MyD88-dependent pathway, in contrast to TLR3-induced IFN-alpha production, which is entirely TRIF-dependent. There is also a distinct requirement for IFN regulatory factors (IRFs), with LPS-induced IFN-alpha induction being entirely IRF7- and partially IRF5-dependent, in contrast to LPS-induced IFN-beta gene induction which is known to be IRF3-dependent but largely IRF7-independent. This data demonstrates a novel pathway for IFN-alpha production by cDCs and provides one possible explanation for how bacterial infection might precipitate disease flares in SLE.
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Richez
authors.forename: Kei
authors.initials: K
authors.lastname: Yasuda
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Watkins
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.forename: Jean M
authors.initials: JM
authors.lastname: van Seventer
authors.forename: Ian R
authors.initials: IR
authors.lastname: Rifkin
mesh_terms: D000818:Animals; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000502:physiology; D016899:Interferon-beta / Q000502:physiology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D016898:Interferon-alpha; D008024:Ligands; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta