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