Interleukin-1 and interferon-γ orchestrate β-glucan-activated human dendritic cell programming via IκB-ζ modulation

• Published in: PloS one Vol. 9; no. 12; p. e114516
• Main Authors: Cardone, Marco, Dzutsev, Amiran K, Li, Hongchuan, Riteau, Nicolas, Gerosa, Franca, Shenderov, Kevin, Winkler-Pickett, Robin, Provezza, Lisa, Riboldi, Elena, Leighty, Robert M, Orr, Selinda J, Steinhagen, Folkert, Wewers, Mark D, Sher, Alan, Anderson, Stephen K, Goldszmid, Romina, McVicar, Daniel W, Lyakh, Lyudmila, Trinchieri, Giorgio
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.12.2014; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; Adaptor Proteins, Signal Transducing; Autoimmune diseases; beta-Glucans - pharmacology; Biology and Life Sciences; Biomedical research; Cancer; Cell adhesion; Cells, Cultured; Cytokines; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Fungi; Gene expression; Glucan; Helper cells; Humans; I-kappa B Proteins - metabolism; Immune response (cell-mediated); Immunity; Immunology; Infectious diseases; Inflammasomes; Inflammation; Interferon; Interferon-gamma - physiology; Interleukin 1; Interleukin 1 Receptor Antagonist Protein - physiology; Interleukin 17; Interleukin 22; Interleukin-1 - physiology; Interleukin-23 Subunit p19 - genetics; Interleukin-23 Subunit p19 - metabolism; Kinases; Laboratories; Lipopolysaccharides - pharmacology; Lymphocytes; Lymphocytes T; Medical research; Medicine and Health Sciences; Microorganisms; Modulation; Nitric oxide; Nuclear Proteins - metabolism; Parasitic diseases; Positive feedback; Programming; Promoter Regions, Genetic; Receptors; Regulation; Science programs; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Transcription; Transcription, Genetic; Transcriptional Activation; Transcriptome; Tuberculosis; Tumor necrosis factor-TNF; Yeasts; β-Glucan; γ-Interferon; Italy; Ohio; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114516

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.