IL-1 receptor-associated kinase 4 is essential for IL-18-mediated NK and Th1 cell responses.
IL-18 is an important cytokine for both innate and adaptive immunity. NK T cells and Th1 cells depend on IL-18 for their divergent functions. The IL-18R, IL-1R, and mammalian Toll-like receptors (TLRs) share homologous intracellular domains known as the TLR/IL-1R/plant R domain. Previously, we reported that IL-1R-associated kinase (IRAK)-4 plays a critical role in IL-1R and TLR signaling cascades and is essential for the innate immune response. Because TLR/IL-1R/plant R-containing receptors mediate signal transduction in a similar fashion, we investigated the role of IRAK-4 in IL-18R signaling. In this study, we show that IL-18-induced responses such as NK cell activity, Th1 IFN-gamma production, and Th1 cell proliferation are severely impaired in IRAK-4-deficient mice. IRAK-4(-/-) Th1 cells also do not exhibit NF-kappaB activation or IkappaB degradation in response to IL-18. Moreover, AP-1 activation which is triggered by c-Jun N-terminal kinase activation is also completely inhibited in IRAK-4(-/-) Th1 cells. These results suggest that IRAK-4 is an essential component of the IL-18 signaling cascade.
Suzuki
Nobutaka
N
Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Chen
Nien-Jung
NJ
Millar
Douglas G
DG
Suzuki
Shinobu
S
Horacek
Thomas
T
Hara
Hiromitsu
H
Bouchard
Denis
D
Nakanishi
Kenji
K
Penninger
Josef M
JM
Ohashi
Pamela S
PS
Yeh
Wen-Chen
WC
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D053592:Interleukin-1 Receptor-Associated Kinases; D020382:Interleukin-18 / Q000378:metabolism / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D053724:Receptors, Interleukin-18; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology
C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; D007371:Interferon-gamma; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse