Bruton's tyrosine kinase and protein kinase C µ are required for TLR7/9-induced IKKα and IRF-1 activation and interferon-β production in conventional dendritic cells

PLoS One. 2014 Aug 29;9(8):e105420. doi: 10.1371/journal.pone.0105420. eCollection 2014.

Abstract

Stimulation of TLR7/9 by their respective ligands leads to the activation of IκB kinase α (IKKα) and Interferon Regulatory Factor 1 (IRF-1) and results in interferon (IFN)-β production in conventional dendritic cells (cDC). However, which other signaling molecules are involved in IKKα and IRF-1 activation during TLR7/9 signaling pathway are not known. We and others have shown that Bruton's Tyrosine Kinase (BTK) played a part in TLR9-mediated cytokine production in B cells and macrophages. However, it is unclear if BTK participates in TLR7/9-induced IFN-β production in cDC. In this study, we show that BTK is required for IFN-β synthesis in cDC upon TLR7/9 stimulation and that stimulated BTK-deficient cDC are defective in the induction of IKKα/β phosphorylation and IRF-1 activation. In addition, we demonstrate that Protein Kinase C µ (PKCµ) is also required for TLR7/9-induced IRF-1 activation and IFN-β upregulation in cDC and acts downstream of BTK. Taken together, we have uncovered two new molecules, BTK and PKCµ, that are involved in TLR7/9-triggered IFN-β production in cDC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Gene Deletion
  • I-kappa B Kinase / immunology*
  • Interferon Regulatory Factor-1 / immunology*
  • Interferon-beta / immunology*
  • Mice, Inbred C57BL
  • Protein Kinase C / immunology*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / immunology*
  • Toll-Like Receptor 7 / immunology*
  • Toll-Like Receptor 9 / immunology*

Substances

  • Interferon Regulatory Factor-1
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Interferon-beta
  • protein kinase D
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • Btk protein, mouse
  • I-kappa B Kinase
  • Protein Kinase C

Grants and funding

Biomedical Research Council of the Singapore Agency for Science Technology and Research (http://www.a-star.edu.sg/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.