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Negative regulation of Toll-like-receptor signaling by IRF-4
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 102(44)
- Publication Year :
- 2005
-
Abstract
- 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.
- Subjects :
- Cell signaling
Interferon Regulatory Factor-7
Biology
Proinflammatory cytokine
Mice
Hypersensitivity
Animals
Receptors, Immunologic
Transcription factor
Adaptor Proteins, Signal Transducing
Regulation of gene expression
Mice, Knockout
Toll-like receptor
Multidisciplinary
Toll-Like Receptors
Biological Sciences
Antigens, Differentiation
Cell biology
Gene Expression Regulation
Interferon Regulatory Factors
Myeloid Differentiation Factor 88
Macrophages, Peritoneal
Cytokines
Signal transduction
IRF4
Signal Transduction
Subjects
Details
- ISSN :
- 00278424
- Volume :
- 102
- Issue :
- 44
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....575a8a96a602129db2076f27c3ed3d73