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IFN-? abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling.

ABSTRACT: An important mechanism by which IFN-? primes macrophages for enhanced innate immune responses is abrogation of feedback inhibitory pathways. Accordingly, IFN-? abrogates endotoxin tolerance, a major negative feedback loop that silences expression of inflammatory cytokine genes in macrophages previously exposed to endotoxin/Toll-like receptor (TLR) ligands. Mechanisms by which IFN-? inhibits endotoxin tolerance have not been elucidated. Here, we show that pretreatment with IFN-? prevented tolerization of primary human monocytes and restored TLR4-mediated induction of various proinflammatory cytokines, including IL-6 and TNF?. Surprisingly, IFN-? did not alter proximal TLR4 signaling defects in tolerized monocytes. Instead, IFN-? blocked tolerance-associated down-regulation of IL6 and TNF transcription, RNA polymerase II recruitment, and NF-?B and CCAAT/enhancer-binding protein ? transcription factor binding to the IL6 and TNF promoters in tolerized monocytes. The mechanism by which IFN-? restored IL6 expression was by facilitating TLR4-induced recruitment of chromatin remodeling machinery to the IL6 promoter and promoting IL6 locus accessibility in tolerized monocytes. Our results suggest that IFN-? overcomes endotoxin tolerance by facilitating TLR-induced chromatin remodeling to allow expression of proinflammatory genes. These results identify a mechanism by which IFN-? promotes activation of macrophages and highlight the importance of chromatin remodeling and transcriptional control in the regulation of inflammatory cytokine production in tolerant and activated macrophages.

SUBMITTER: Chen J

PROVIDER: S-EPMC2984206 | biostudies-other | 2010 Nov

REPOSITORIES: biostudies-other

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IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling.

Chen Janice J Ivashkiv Lionel B LB

Proceedings of the National Academy of Sciences of the United States of America 20101025 45

An important mechanism by which IFN-γ primes macrophages for enhanced innate immune responses is abrogation of feedback inhibitory pathways. Accordingly, IFN-γ abrogates endotoxin tolerance, a major negative feedback loop that silences expression of inflammatory cytokine genes in macrophages previously exposed to endotoxin/Toll-like receptor (TLR) ligands. Mechanisms by which IFN-γ inhibits endotoxin tolerance have not been elucidated. Here, we show that pretreatment with IFN-γ prevented toleriz ...[more]

PMID: 20974955

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Project description:Endotoxin tolerance reprograms cell responses to LPS by repressing expression of proinflammatory cytokines, while not inhibiting production of anti-inflammatory cytokines and antimicrobial effectors. Molecular mechanisms of induction and maintenance of endotoxin tolerance are incompletely understood, particularly with regard to the impact of endotoxin tolerization on signalosome assembly, activation of adaptor-kinase modules, and expression of negative regulators of TLR signaling in human cells. In this study, we examined LPS-mediated activation of MyD88-dependent and Toll-IL-1R-containing adaptor inducing IFN-beta (TRIF)-dependent pathways emanating from TLR4 and expression of negative regulators of TLR signaling in control and endotoxin-tolerant human monocytes. Endotoxin tolerization suppressed LPS-inducible TLR4-TRIF and TRIF-TANK binding kinase (TBK)1 associations, induction of TBK1 kinase activity, activation of IFN regulatory factor (IRF)-3, and expression of RANTES and IFN-beta. Tolerance-mediated dysregulation of the TLR4-TRIF-TBK1 signaling module was accompanied by increased levels of suppressor of IkappaB kinase-epsilon (SIKE) and sterile alpha and Armadillo motif-containing molecule (SARM). LPS-tolerant cells showed increased expression of negative regulators Toll-interacting protein (Tollip), suppressor of cytokine signaling (SOCS)-1, IL-1R-associated kinase-M, and SHIP-1, which correlated with reduced p38 phosphorylation, IkappaB-alpha degradation, and inhibited expression of TNF-alpha, IL-6, and IL-8. To examine functional consequences of increased expression of Tollip in LPS-tolerized cells, we overexpressed Tollip in 293/TLR4/MD-2 transfectants and observed blunted LPS-inducible activation of NF-kappaB and RANTES, while TNF-alpha responses were not affected. These data demonstrate dysregulation of TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increased expression of negative regulators of TLR signaling in endotoxin-tolerant human monocytes.

Dataset Information

IFN-? abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling.

Publications

IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling.

Similar Datasets

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