title: A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity.
abstract: IRAK4 is a member of IL-1 receptor (IL-1R)-associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)-mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase-inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinflammatory cytokines and chemokines. Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R-mediated nuclear factor kappaB activation, a reduction of LPS-, R848-, and IL-1-mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow-derived macrophages from IRAK4 kinase-inactive knock-in mice. Both TLR7- and TLR9-mediated type I interferon production was abolished in plasmacytoid dendritic cells isolated from IRAK4 knock-in mice. In addition, influenza virus-induced production of interferons in plasmacytoid DCs was also dependent on IRAK4 kinase activity. Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, Indianapolis, IN 46285, USA.
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.forename: Kirk
authors.initials: K
authors.lastname: Staschke
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.forename: Jianhong
authors.initials: J
authors.lastname: Yao
authors.forename: Kristi
authors.initials: K
authors.lastname: Peters
authors.forename: Keun-Hee
authors.initials: KH
authors.lastname: Oh
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Vandenburg
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Wen
authors.initials: W
authors.lastname: Qian
authors.forename: Tom
authors.initials: T
authors.lastname: Hamilton
authors.forename: Booki
authors.initials: B
authors.lastname: Min
authors.forename: Ganes
authors.initials: G
authors.lastname: Sen
authors.forename: Raymond
authors.initials: R
authors.lastname: Gilmour
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007113:Immunity, Innate / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D016207:Cytokines; D017931:DNA Primers; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases