IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling.
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 tolerization of primary human monocytes and restored TLR4-mediated induction of various proinflammatory cytokines, including IL-6 and TNFα. Surprisingly, IFN-γ did not alter proximal TLR4 signaling defects in tolerized monocytes. Instead, IFN-γ blocked tolerance-associated down-regulation of IL6 and TNF transcription, RNA polymerase II recruitment, and NF-κB and CCAAT/enhancer-binding protein β transcription factor binding to the IL6 and TNF promoters in tolerized monocytes. The mechanism by which IFN-γ 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-γ overcomes endotoxin tolerance by facilitating TLR-induced chromatin remodeling to allow expression of proinflammatory genes. These results identify a mechanism by which IFN-γ 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.
Chen
Janice
J
Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
Ivashkiv
Lionel B
LB
D001773:Blood Cells; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D016207:Cytokines / Q000096:biosynthesis; D004731:Endotoxins / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology*; D007963:Leukocytes, Mononuclear; D008262:Macrophage Activation / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology*; D014158:Transcription, Genetic
D016207:Cytokines; D004731:Endotoxins; D051193:Toll-Like Receptors; D007371:Interferon-gamma