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

PLoS One. 2014 Dec 4;9(12):e114516. doi: 10.1371/journal.pone.0114516. eCollection 2014.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cells, Cultured
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Humans
  • I-kappa B Proteins / metabolism*
  • Interferon-gamma / physiology*
  • Interleukin 1 Receptor Antagonist Protein / physiology
  • Interleukin-1 / physiology*
  • Interleukin-23 Subunit p19 / genetics
  • Interleukin-23 Subunit p19 / metabolism
  • Lipopolysaccharides / pharmacology
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • Transcriptome
  • beta-Glucans / pharmacology*

Substances

  • I-kappa B Proteins
  • IL23A protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Interleukin-23 Subunit p19
  • Lipopolysaccharides
  • NFKBIZ protein, human
  • Nuclear Proteins
  • beta-Glucans
  • Interferon-gamma