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J Biol Chem. 2007 Sep 14;282(37):26857-64. Epub 2007 Jul 23.

Epigenetic silencing of tumor necrosis factor alpha during endotoxin tolerance.

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1
Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. melgazza@wfubmc.edu

Abstract

Sustained silencing of potentially autotoxic acute proinflammatory genes like tumor necrosis factor alpha (TNFalpha) 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 TNFalpha proximal promoter nucleosomes and transcription factors adapt to an activation-specific profile by developing characteristic chromatin-based silencing marks. We found increased TNFalpha mRNA levels in endotoxin-responsive cells that was preceded by dissociation of heterochromatin-binding protein 1alpha, demethylation of nucleosomal histone H3 lysine 9 (H3(Lys(9))), increased phosphorylation of the adjacent serine 10 (H3(Ser(10))), and recruitment of NF-kappaB RelA/p65 to the TNFalpha promoter. In contrast, endotoxin-tolerant cells repressed production of TNFalpha mRNA, retained binding of heterochromatin-binding protein 1alpha, sustained methylation of H3(Lys(9)), reduced phosphorylation of H3(Ser(10)), and showed diminished binding of NF-kappaB RelA/p65 to the TNFalpha promoter. Similar levels of NF-kappaB p50 occurred at the TNFalpha promoter in the basal state, during active transcription, and in the silenced phenotype. RelB, which acts as a repressor of TNFalpha 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.

PMID:
17646159
DOI:
10.1074/jbc.M704584200
[Indexed for MEDLINE]
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