title: Interleukin-1 and interferon-γ orchestrate β-glucan-activated human dendritic cell programming via IκB-ζ modulation.
abstract: Recognition of microbial components via innate receptors including the C-type lectin receptor Dectin-1, together with the inflammatory environment, programs dendritic cells (DCs) to orchestrate the magnitude and type of adaptive immune responses. The exposure to β-glucan, a known Dectin-1 agonist and component of fungi, yeasts, and certain immune support supplements, activates DCs to induce T helper (Th)17 cells that are essential against fungal pathogens and extracellular bacteria but may trigger inflammatory pathology or autoimmune diseases. However, the exact mechanisms of DC programming by β-glucan have not yet been fully elucidated. Using a gene expression/perturbation approach, we demonstrate that in human DCs β-glucan transcriptionally activates via an interleukin (IL)-1- and inflammasome-mediated positive feedback late-induced genes that bridge innate and adaptive immunity. We report that in addition to its known ability to directly prime T cells toward the Th17 lineage, IL-1 by promoting the transcriptional cofactor inhibitor of κB-ζ (IκB-ζ) also programs β-glucan-exposed DCs to express cell adhesion and migration mediators, antimicrobial molecules, and Th17-polarizing factors. Interferon (IFN)-γ interferes with the IL-1/IκB-ζ axis in β-glucan-activated DCs and promotes T cell-mediated immune responses with increased release of IFN-γ and IL-22, and diminished production of IL-17. Thus, our results identify IL-1 and IFN-γ as regulators of DC programming by β-glucan. These molecular networks provide new insights into the regulation of the Th17 response as well as new targets for the modulation of immune responses to β-glucan-containing microorganisms.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Marco
authors.initials: M
authors.lastname: Cardone
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Amiran K
authors.initials: AK
authors.lastname: Dzutsev
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Li
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Riteau
authors.affiliation: Department of Pathology, University of Verona, Verona, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Gerosa
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shenderov
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Robin
authors.initials: R
authors.lastname: Winkler-Pickett
authors.affiliation: Department of Pathology, University of Verona, Verona, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Provezza
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Elena
authors.initials: E
authors.lastname: Riboldi
authors.affiliation: Data Management Services, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Leighty
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Selinda J
authors.initials: SJ
authors.lastname: Orr
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Folkert
authors.initials: F
authors.lastname: Steinhagen
authors.affiliation: The Ohio State University, Davis Heart and Lung Research Institute, Columbus, Ohio, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Anderson
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Romina
authors.initials: R
authors.lastname: Goldszmid
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McVicar
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Lyakh
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America; The Trans-NIH Center for Human Immunology, Bethesda, Maryland, United States of America.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trinchieri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000502:physiology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D059467:Transcriptome; D047071:beta-Glucans / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; C508840:IL23A protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053760:Interleukin-23 Subunit p19; D008070:Lipopolysaccharides; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D047071:beta-Glucans; D007371:Interferon-gamma