A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity.
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.
Kim
Tae Whan
TW
Department of Immunology, Cleveland Clinic Foundation, Indianapolis, IN 46285, USA.
Staschke
Kirk
K
Bulek
Katarzyna
K
Yao
Jianhong
J
Peters
Kristi
K
Oh
Keun-Hee
KH
Vandenburg
Yvonne
Y
Xiao
Hui
H
Qian
Wen
W
Hamilton
Tom
T
Min
Booki
B
Sen
Ganes
G
Gilmour
Raymond
R
Li
Xiaoxia
X
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*
D016207:Cytokines; D017931:DNA Primers; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases