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Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors
- Source :
- Nature. 434:243-249
- Publication Year :
- 2005
- Publisher :
- Springer Science and Business Media LLC, 2005.
-
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.
- Subjects :
- Lipopolysaccharides
medicine.medical_treatment
Receptors, Cell Surface
Biology
Proinflammatory cytokine
Mice
medicine
Animals
RNA, Messenger
Receptors, Immunologic
Promoter Regions, Genetic
Transcription factor
Adaptor Proteins, Signal Transducing
Inflammation
TNF Receptor-Associated Factor 6
Toll-like receptor
Membrane Glycoproteins
Multidisciplinary
Innate immune system
Toll-Like Receptors
Acquired immune system
Antigens, Differentiation
Shock, Septic
Up-Regulation
Cell biology
Cytokine
Interferon Regulatory Factors
Myeloid Differentiation Factor 88
Immunology
Cytokines
Signal transduction
Gene Deletion
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 14764687 and 00280836
- Volume :
- 434
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....a07022f29fff934e75e64877361573aa