title: The dual functions of IL-1 receptor-associated kinase 2 in TLR9-mediated IFN and proinflammatory cytokine production.
abstract: Bone marrow-derived plasmacytoid dendritic cells (pDCs) from IL-1R-associated kinase (IRAK)2-deficient mice produced more IFNs than did wild-type pDCs upon stimulation with the TLR9 ligand CpG. Furthermore, in CpG-stimulated IRAK2-deficient pDCs there was increased nuclear translocation of IFN regulatory factor 7, the key transcription factor for IFN gene transcription in these cells. In IRAK2-deficient macrophages, enhanced NF-κB activation and increased expression of CpG-induced genes were detected within 2 h after treatment. However, at later times, NF-κB activation was decreased and, in contrast to the results with IFN, there was less secretion of other proinflammatory cytokines (such as TNF-α) and chemokines in CpG-stimulated IRAK2-deficient pDCs and macrophages. Therefore, although IRAK2 is a negative regulator of TLR9-mediated IFN production through its modulation of the transcriptional activity of IFN regulatory factor 7, it is also a positive regulator of TLR9-mediated proinflammatory cytokine and chemokine production at some level subsequent to transcription.
authors.affiliation: Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Youzhong
authors.initials: Y
authors.lastname: Wan
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.forename: Minjia
authors.initials: M
authors.lastname: Yu
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Michifumi
authors.initials: M
authors.lastname: Yamashita
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Kang
authors.forename: Weiguo
authors.initials: W
authors.lastname: Yin
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Thomas
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D006566:Herpesviridae Infections / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors / Q000502:physiology; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016898:Interferon-alpha; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000502:physiology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins; D018144:Rhadinovirus / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000378:metabolism / Q000502:physiology*; D014412:Tumor Virus Infections / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016898:Interferon-alpha; C494235:Irf7 protein, mouse; D008024:Ligands; D011994:Recombinant Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C068567:interferon alpha 4A; D016899:Interferon-beta; D053592:Interleukin-1 Receptor-Associated Kinases