IL-1R-associated kinase 4 is required for lipopolysaccharide-induced activation of APC.
The bacterial product LPS is a critical stimulus for the host immune system in the response against the corresponding bacterial infection. LPS provides an activation stimulus for macrophages and a maturation signal for dendritic cells to set up innate and adaptive immune responses, respectively. The signaling cascade of myeloid differentiation factor 88-->IL-1R-associated kinase (IRAK)-->TNFR-associated factor 6 has been implicated in mediating LPS signaling. In this report, we studied the function of IRAK-4 in various LPS-induced signals. We found that IRAK-4-deficient cells were severely impaired in producing some IFN-regulated genes as well as inflammatory cytokines in response to LPS. Among the critical downstream signaling pathways induced by LPS, NF-kappaB activation but not IFN regulatory factor 3 or STAT1 activation was defective in cells lacking IRAK-4. IRAK-4 was also required for the proper maturation of dendritic cells by LPS stimulation, particularly in terms of cytokine production and the ability to stimulate Th cell differentiation. Our results demonstrate that IRAK-4 is critical for the LPS-induced activations of APCs.
Suzuki
Nobutaka
N
Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Suzuki
Shinobu
S
Eriksson
Urs
U
Hara
Hiromitsu
H
Mirtosis
Christine
C
Chen
Nien-Jung
NJ
Wada
Teiji
T
Bouchard
Denis
D
Hwang
Irene
I
Takeda
Kiyoshi
K
Fujita
Takashi
T
Der
Sandy
S
Penninger
Josef M
JM
Akira
Shizuo
S
Saito
Takashi
T
Yeh
Wen-Chen
WC
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016899:Interferon-beta / Q000096:biosynthesis; D053592:Interleukin-1 Receptor-Associated Kinases; D007519:Isoantigens / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D007519:Isoantigens; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D016899:Interferon-beta; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse