IRAK4 turns IL-10+ phospho-FOXO+ monocytes into pro-inflammatory cells by suppression of protein kinase B

Eur J Immunol. 2013 Jun;43(6):1630-42. doi: 10.1002/eji.201243217. Epub 2013 Apr 30.

Abstract

IRAK4, a serine/threonine kinase is a central adaptor protein in TLR signaling. To better understand the clinical significance of IRAK4 deficiency we examined the impact of IRAK4 on bacterial recognition in human monocytes. We show that IRAK4 knockdown modulates monocyte-derived cytokine secretion in response to Staphylococcus aureus and Streptococcus pneumoniae, resulting in decreased IL-12 and elevated IL-10 production, a finding also reproducible with ligands for TLR2 and TLR4. In contrast, silencing of MyD88 leads to a complete loss of cytokine secretion, indicating that IRAK4 acts as a differential regulator of bacteria/TLR-induced cytokine secretion downstream of MyD88. Further analysis revealed that this modulatory function results from IRAK4-mediated suppression of protein kinase B (PKB/Akt). Release of suppression upon IRAK4 silencing (but not MyD88 knockdown) increases phosphorylation of PKB/Akt, counteracts NF-κB activation and finally results in a monocyte phenotype with tolerogenic features, thus unleashing Akt- and mTOR-dependent release of IL-10, along with concomitant phosphorylation of FOXO transcription factors. In line with these observations IRAK4-deficient monocytes failed to induce allogeneic CD8(+) and CD4(+) T-cell responses, an effect reverted by neutralization of IL-10. Taken together, our data highlight an unexpected role of IRAK4, Akt, and mTOR in the regulation of tolerance in human monocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Cells, Cultured
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / immunology*
  • Interleukin-10 / metabolism
  • Interleukin-12 / metabolism
  • Lymphocyte Activation / genetics
  • Monocytes / immunology*
  • Monocytes / microbiology
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • NF-kappa B / metabolism
  • Oncogene Protein v-akt / metabolism
  • Pneumococcal Infections / immunology*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Staphylococcal Infections / immunology*
  • Staphylococcus aureus / immunology*
  • Streptococcus pneumoniae / immunology*
  • TOR Serine-Threonine Kinases / immunology

Substances

  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • RNA, Small Interfering
  • Interleukin-10
  • Interleukin-12
  • 3-Phosphoinositide-Dependent Protein Kinases
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Oncogene Protein v-akt
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases