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.
Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
Janice
J
Chen
Lionel B
LB
Ivashkiv
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