title: IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses.
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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lye
authors.forename: Salim
authors.initials: S
authors.lastname: Dhanji
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D006023:Glycoproteins / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology; D010457:Peptidoglycan / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013682:Teichoic Acids / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology
chemical_list: D000956:Antigens, Viral; C408982:CPG-oligonucleotide; D006023:Glycoproteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D010457:Peptidoglycan; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; C009900:lipoteichoic acid; D007371:Interferon-gamma; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse