Abstract
The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity. All TLRs use the adaptor MyD88 for signalling, but the mechanisms underlying the MyD88-mediated gene induction programme are as yet not fully understood. Here, we demonstrate that the transcription factor IRF-5 is generally involved downstream of the TLR-MyD88 signalling pathway for gene induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 gene (Irf5-/- mice), the induction of these cytokines by various TLR ligands is severely impaired, whereas interferon-alpha induction is normal. We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6, and that TLR activation results in the nuclear translocation of IRF-5 to activate cytokine gene transcription. Consistently, Irf5-/- mice show resistance to lethal shock induced by either unmethylated DNA or lipopolysaccharide, which correlates with a marked decrease in the serum levels of proinflammatory cytokines. Thus, our study identifies IRF-5 as a new, principal downstream regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism
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Cytokines / biosynthesis
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Cytokines / genetics*
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Cytokines / metabolism
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Gene Deletion
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Inflammation / genetics
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Inflammation / metabolism
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Interferon Regulatory Factors
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Lipopolysaccharides / pharmacology
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Membrane Glycoproteins / metabolism*
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Mice
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Myeloid Differentiation Factor 88
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / deficiency
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism
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Shock, Septic / chemically induced
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Shock, Septic / genetics
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Signal Transduction*
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TNF Receptor-Associated Factor 6 / metabolism
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Toll-Like Receptors
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Up-Regulation*
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Cytokines
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Interferon Regulatory Factors
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Irf5 protein, mouse
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Lipopolysaccharides
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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RNA, Messenger
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Receptors, Cell Surface
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Receptors, Immunologic
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TNF Receptor-Associated Factor 6
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Toll-Like Receptors
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Transcription Factors