title: Human plasmacytoid dendritic cells regulate IFN-α production through activation-induced splicing of IL-18Rα.
abstract: IFN-α production by pDCs regulates host protection against viruses and is implicated in autoimmune pathology. Human pDCs express high levels of IL-18R, but little is known of its role in pDC function. We report that IL-18R signaling negatively regulates IFN-α production through activation-induced splicing of IL-18Rα in human pDCs. Our data reveal two distinct isoforms of IL-18Rα in human pDCs: the known, full-length receptor (IL-18Rα1) and a novel, truncated variant (IL-18Rα2), which functions as a molecular decoy that competitively inhibits the canonical IL-18Rα1/IL-18Rβ signaling pathway. Whereas NK cells and pDCs both express IL-18Rα1, pDCs express significantly higher levels of IL-18Rα2, resulting in differential responses of these populations to IL-18. Flu exposure increases IL-18Rα1 expression in pDCs, and the blocking of IL-18R enhances pDC production of IFN-α and IP-10; thus, pDCs use activation-induced splicing to regulate IFN-α production in response to flu. These data demonstrate that IL-18R modulates IFN-α release by human pDCs and suggest that IL-18R signaling may represent a promising therapeutic target.
authors.affiliation: Singapore Immunology Network and.
authors.forename: Yinxia
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Singapore Immunology Network and Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Biopolis, Singapore;
authors.forename: Nivashini
authors.initials: N
authors.lastname: Kaliaperumal
authors.affiliation: Singapore Immunology Network and.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Chretien
authors.affiliation: Singapore Immunology Network and.
authors.forename: Suisheng
authors.initials: S
authors.lastname: Tang
authors.affiliation: Singapore Immunology Network and.
authors.forename: Bernett
authors.initials: B
authors.lastname: Lee
authors.affiliation: Singapore Immunology Network and.
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.affiliation: Singapore Immunology Network and Department of Immunology, University of Texas Southwestern Medical Center at Dallas, Texas, USA; and.
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Fairhurst
authors.affiliation: Singapore Immunology Network and Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Biopolis, Singapore; Institute of Biomedical Studies, Baylor University, Waco, Texas, USA jeconnolly@imcb.a-star.edu.sg.
authors.forename: John E
authors.initials: JE
authors.lastname: Connolly
mesh_terms: D001483:Base Sequence; D001667:Binding, Competitive; D002454:Cell Differentiation; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D053724:Receptors, Interleukin-18 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016898:Interferon-alpha; D020382:Interleukin-18; D020033:Protein Isoforms; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: anti-viral response; inflammation; innate immunity