IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses

Eur J Immunol. 2008 Mar;38(3):870-6. doi: 10.1002/eji.200737429.

Abstract

Interleukin-1 receptor-associated kinase (IRAK)-4 is a serine-threonine kinase that plays an important role in innate and adaptive immune responses. While the requirement of IRAK-4 kinase activity has been studied in the context of IL-1R signaling, it is not clear whether IRAK-4 requires its kinase function for all of its roles in the immune system. IRAK-4 kinase-dead knock-in (IRAK-4KD/KD) mice were generated to further elucidate whether IRAK-4 kinase activity is required for IRAK-4 to induce cytokine production. IRAK-4KD/KD mice were impaired in their ability to produce cytokines in response to in vivo challenge with lipopolysaccharide (LPS), a potent TLR4 ligand. Cytokine production was also reduced in macrophages and dendritic cells from IRAK-4KD/KD mice in response to LPS and other TLR ligands. In addition, adaptive immune responses were impaired in IRAK-4KD/KD mice. Although in vitro T cell proliferation in response to TCR activation was unaffected in IRAK-4-deficient mice, in vivo T cell responses to lymphocytic choriomeningitits virus infection were significantly impaired in IRAK-4-knockout mice or mice expressing the kinase-dead mutant of IRAK-4. Collectively, these results indicate that IRAK-4 kinase activity is required for IRAK-4-dependent signaling in innate and adaptive immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Viral / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Glycoproteins / immunology
  • Immunity, Cellular / immunology*
  • Immunity, Innate / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Interleukin-6 / blood
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation / immunology
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mice, Transgenic
  • Oligodeoxyribonucleotides / pharmacology
  • Peptide Fragments / immunology
  • Peptidoglycan / pharmacology
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / virology
  • T-Lymphocytes, Cytotoxic / immunology
  • Teichoic Acids / pharmacology
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / metabolism
  • Viral Proteins / immunology

Substances

  • Antigens, Viral
  • CPG-oligonucleotide
  • Glycoproteins
  • Interleukin-6
  • Lipopolysaccharides
  • Oligodeoxyribonucleotides
  • Peptide Fragments
  • Peptidoglycan
  • Teichoic Acids
  • Tumor Necrosis Factor-alpha
  • Viral Proteins
  • glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus
  • lipoteichoic acid
  • Interferon-gamma
  • Interleukin-1 Receptor-Associated Kinases
  • Irak4 protein, mouse