Sustained silencing of potentially autotoxic acute proinflammatory genes like tumor necrosis factor α (TNFα) occurs in circulating leukocytes following the early phase of severe systemic inflammation. Aspects of this gene reprogramming suggest the involvement of epigenetic processes. We used THP-1 human promonocytes, which mimic gene silencing when rendered endotoxin-tolerant in vitro, to test whether TNFα proximal promoter nucleosomes and transcription factors adapt to an activation-specific profile by developing characteristic chromatin-based silencing marks. We found increased TNFα mRNA levels in endotoxin-responsive cells that was preceded by dissociation of heterochromatin-binding protein 1α, demethylation of nucleosomal histone H3 lysine 9 (H3(Lys9)), increased phosphorylation of the adjacent serine 10 (H3(Ser10)), and recruitment of NF-κB RelA/p65 to the TNFα promoter. In contrast, endotoxintolerant cells repressed production of TNFα mRNA, retained binding of heterochromatin-binding protein 1α, sustained methylation of H3(Lys9), reduced phosphorylation of H3(Ser10), and showed diminished binding of NF-κB RelA/p65 to the TNFα promoter. Similar levels of NF-κB p50 occurred at the TNFα promoter in the basal state, during active transcription, and in the silenced phenotype. RelB, which acts as a repressor of TNFα transcription, remained bound to the promoter during silencing. These results support an immunodeficiency paradigm where epigenetic changes at the promoter of acute proinflammatory genes mediate their repression during the late phase of severe systemic inflammation.
This work was supported by National Institutes of Health Grants RO1AI-09169 and RO1AI-065791. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
