title: IFNα enhances the production of IL-6 by human neutrophils activated via TLR8.
abstract: Recently, we reported that human neutrophils produce biologically active amounts of IL-6 when incubated with agonists activating TLR8, a receptor recognizing viral single strand RNA. In this study, we demonstrate that IFNα, a cytokine that modulates the early innate immune responses toward viral and bacterial infections, potently enhances the production of IL-6 in neutrophils stimulated with R848, a TLR8 agonist. We also show that such an effect is not caused by an IFNα-dependent induction of TLR7 and its consequent co-activation with TLR8 in response to R848, but, rather, it is substantially mediated by an increased production and release of endogenous TNFα. The latter cytokine, in an autocrine manner, leads to an augmented synthesis of the IkBζ co-activator and an enhanced recruitment of the C/EBPβ transcription factor to the IL-6 promoter. Moreover, we show that neutrophils from SLE patients with active disease state, hence displaying an IFN-induced gene expression signature, produce increased amounts of both IL-6 and TNFα in response to R848 as compared to healthy donors. Altogether, data uncover novel effects that type I IFN exerts in TLR8-activated neutrophils, which therefore enlarge our knowledge on the various biological actions which type I IFN orchestrates during infectious and autoimmune diseases.
authors.affiliation: Department of Medicine, Division of General Pathology, University of Verona, Verona, Italy.
authors.forename: Maili
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Medicine, Division of General Pathology, University of Verona, Verona, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Arruda-Silva
authors.affiliation: Department of Medicine, Division of General Pathology, University of Verona, Verona, Italy.
authors.forename: Francisco
authors.initials: F
authors.lastname: Bianchetto-Aguilera
authors.affiliation: Department of Medicine, Division of General Pathology, University of Verona, Verona, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Finotti
authors.affiliation: Department of Medicine, Division of General Pathology, University of Verona, Verona, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Calzetti
authors.affiliation: Department of Medicine, Division of General Pathology, University of Verona, Verona, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Scapini
authors.affiliation: Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Lunardi
authors.affiliation: Department of Medicine, Division of General Pathology, University of Verona, Verona, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cassatella
authors.affiliation: Department of Medicine, Division of General Pathology, University of Verona, Verona, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
mesh_terms: D000328:Adult; D000368:Aged; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056426:Genetic Loci; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D007093:Imidazoles; D016898:Interferon-alpha; D015850:Interleukin-6; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; C402365:resiquimod