Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5
Open Access
- 6 February 2012
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 209 (2), 379-393
- https://doi.org/10.1084/jem.20111569
Abstract
Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of. B kinase (IKK). activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses.This publication has 80 references indexed in Scilit:
- IκBβ acts to inhibit and activate gene expression during the inflammatory responseNature, 2010
- The role of pattern-recognition receptors in innate immunity: update on Toll-like receptorsNature Immunology, 2010
- Pattern Recognition Receptors and InflammationCell, 2010
- Transcriptional Integration of TLR2 and TLR4 Signaling at the NCoR Derepression CheckpointMolecular Cell, 2009
- Control of Inducible Gene Expression by Signal-Dependent Transcriptional ElongationCell, 2009
- A Unifying Model for the Selective Regulation of Inducible Transcription by CpG Islands and Nucleosome RemodelingCell, 2009
- Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signalsNature Immunology, 2009
- The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene SilencingCell, 2007
- A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γNature, 2005
- MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll‐like receptor 2 signalingEuropean Journal of Immunology, 2003