Negative regulation of Toll-like-receptor signaling by IRF-4.

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.

DOI: 10.1073/pnas.0508327102
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@article{Negishi2005NegativeRO, title={Negative regulation of Toll-like-receptor signaling by IRF-4.}, author={Hideo Negishi and Yusuke Ohba and Hideyuki Yanai and Akinori Takaoka and Kiri Honma and Katsuyuki Yui and Toshifumi Matsuyama and Tadatsugu Taniguchi and Kenya Honda}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2005}, volume={102 44}, pages={15989-94} }