title: IL-1R-associated kinase 4 is required for lipopolysaccharide-induced activation of APC.
abstract: 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.
authors.affiliation: Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Suzuki
authors.forename: Shinobu
authors.initials: S
authors.lastname: Suzuki
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.forename: Christine
authors.initials: C
authors.lastname: Mirtosis
authors.forename: Nien-Jung
authors.initials: NJ
authors.lastname: Chen
authors.forename: Teiji
authors.initials: T
authors.lastname: Wada
authors.forename: Denis
authors.initials: D
authors.lastname: Bouchard
authors.forename: Irene
authors.initials: I
authors.lastname: Hwang
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.forename: Sandy
authors.initials: S
authors.lastname: Der
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
mesh_terms: 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
chemical_list: 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