Negative regulation of Toll-like-receptor signaling by IRF-4.
The recognition of microbial components by Toll-like receptors (TLRs) is an event central to the activation of innate and adaptive immune systems. TLR activation triggers the induction of downstream target genes, wherein the TLR-interacting adaptor molecule MyD88 recruits various signaling molecules and transcription factors. Two members of the IFN regulatory factor (IRF) family of transcription factors, IRF-5 and IRF-7, interact with MyD88 and induce proinflammatory cytokines and type I IFNs, respectively. Here, we show that IRF-4 also interacts with MyD88 and acts as a negative regulator of TLR signaling. IRF-4 mRNA is induced by TLR activation, and IRF-4 competes with IRF-5, but not with IRF-7, for MyD88 interaction. The TLR-dependent induction of proinflammatory cytokines is markedly enhanced in peritoneal macrophages from mice deficient in the Irf4 gene, whereas the induction is inhibited by the ectopic expression of IRF-4 in a macrophage cell line. The critical function of IRF-4 in TLR signaling in vivo is underscored by the observation that Irf4-deficient mice show hypersensitivity to DNA-induced shock, with elevated serum proinflammatory cytokine levels. This study may provide an insight into the complex regulatory mechanisms of MyD88 signaling by IRFs.
Negishi
Hideo
H
Department of Immunology, Faculty of Medicine and Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Ohba
Yusuke
Y
Yanai
Hideyuki
H
Takaoka
Akinori
A
Honma
Kiri
K
Yui
Katsuyuki
K
Matsuyama
Toshifumi
T
Taniguchi
Tadatsugu
T
Honda
Kenya
K
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D005786:Gene Expression Regulation; D006967:Hypersensitivity; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D000099218:Interferon Regulatory Factor-4; C498178:Irf5 protein, mouse; C507780:Myd88 protein, mouse