When macrophages are exposed to Toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS, also known as endotoxin), they become activated and produce proinflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF). Subsequent exposure to TLR ligands triggers negative feedback mechanisms that inhibit äthe production of IL-6 and TNF. This decreased sensitivity of cells that have been exposed previously to microbial products, which is termed endotoxin tolerance, helps to prevent tissue damage that is associated with excess inflammation. The proinflammatory cytokine interferon-γ (IFN-γ) activates macrophages and enhances their responses to TLR ligands. In addition, IFN-γ reverses endotoxin tolerance; however, the mechanism involved is unknown. Chen and Ivashkiv hypothesized that IFN-γ might function by interfering with the defects in TLR signaling that occur during tolerance. They showed that, as expected, pretreatment of human monocyte–derived macrophages with IFN-γ blocked the inhibitory effect of repeated exposure to LPS on IL-6 and TNF production. However, IFN-γ did not alter upstream TLR signaling defects, such as diminished mitogen-activated protein kinase (MAPK) activation or defective TLR adaptor molecule assembly, in tolerized cells. Instead, the effects of IFN-γ were observed at the level of gene transcription. The abundances of IL6 and TNF mRNAs were increased in IFN-γ–treated tolerized cells compared with those in untreated tolerized cells, which was associated with restoration of the binding of the transcription factors NF-κB p65 and C/EBPβ to the IL6 and TNF promoters. In addition, IFN-γ increased chromatin accessibility at the IL6 promoter by enhancing the LPS-induced recruitment of the nucleosome-remodeling protein Brg1. Together, these data suggest an alternative mechanism by which IFN-γ promotes the activation of macrophages, which involves transcriptional control.
J. Chen, L. B. Ivashkiv, IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. Proc. Natl. Acad. Sci. U.S.A. 107, 19438–19443 (2010). [Abstract] [Full Text]