title: Endogenously produced TNF-α contributes to the expression of CXCL10/IP-10 in IFN-λ3-activated plasmacytoid dendritic cells.
abstract: The interplay between IFN-λs and dendritic cells is becoming increasingly relevant, particularly in light of their key role in inducing the antiviral state, including in hepatitis C virus infection. In this work, we have analyzed extensively how human plasmacytoid dendritic cells respond to IFN-λ3. We report that plasmacytoid dendritic cells incubated with IFN-λ3 prolong their survival; alter their expression pattern of surface HLA-DRα, CD123, CD86, and CD303; and time dependently produce IFN-α, CXCL10/IFN-γ-induced protein 10, and even modest quantities of TNF-α. Nevertheless, endogenously produced TNF-α, but not IFN-α, was found to be essential for driving the expression of CXCL10/IFN-γ-induced protein 10 in IFN-λ3-treated plasmacytoid dendritic cells, as revealed by neutralizing experiments by use of adalimumab, etanercept, and infliximab. We also observed that based on the kinetics and levels of IFN-α and CXCL10/IFN-γ-induced protein 10 produced by their IFN-λ3-treated plasmacytoid dendritic cells, healthy donors could be categorized into 2 and 3 groups, respectively. In particular, we identified a group of donors whose plasmacytoid dendritic cells produced modest quantities of CXCL10/IFN-γ-induced protein 10; another one whose plasmacytoid dendritic cells produced elevated CXCL10/IFN-γ-induced protein 10 levels, already after 18 h, declining thereafter; and a 3rd group characterized by plasmacytoid dendritic cells releasing very high CXCL10/IFN-γ-induced protein 10 levels after 42 h only. Finally, we report that in plasmacytoid dendritic cells, equivalent concentrations of IFN-λ3 and IFN-λ1 promote survival, antigen modulation, and cytokine production in a comparable manner and without acting additively/synergistically. Altogether, data not only extend the knowledge on the biologic effects that IFN-λs exert on plasmacytoid dendritic cells but also add novel light to the networking between IFN-λs and plasmacytoid dendritic cells in fighting viral diseases.
authors.affiliation: Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Finotti
authors.affiliation: Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.affiliation: Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Calzetti
authors.affiliation: Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Fattovich
authors.affiliation: Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy marco.cassatella@univr.it.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cassatella
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D000954:Antigens, Surface; D054357:Chemokine CXCL10; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: antiviral response; innate immunity; interferons; pDCs