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J. Biol. Chem., Vol. 282, Issue 37, 26857-26864, September 14, 2007

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Epigenetic Silencing of Tumor Necrosis Factor during Endotoxin Tolerance^*

Mohamed El Gazzar¹, Barbara K. Yoza, Jean Y.-Q. Hu, Sue L. Cousart, and Charles E. McCall

From the Department of Internal Medicine, Section of Molecular Medicine, andDepartment of General Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Sustained silencing of potentially autotoxic acute proinflammatory genes like tumor necrosis factor (TNF) 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 TNF proximal promoter nucleosomes and transcription factors adapt to an activation-specific profile by developing characteristic chromatin-based silencing marks. We found increased TNF mRNA levels in endotoxin-responsive cells that was preceded by dissociation of heterochromatin-binding protein 1, demethylation of nucleosomal histone H3 lysine 9 (H3(Lys⁹)), increased phosphorylation of the adjacent serine 10 (H3(Ser¹⁰)), and recruitment of NF-B RelA/p65 to the TNF promoter. In contrast, endotoxintolerant cells repressed production of TNF mRNA, retained binding of heterochromatin-binding protein 1, sustained methylation of H3(Lys⁹), reduced phosphorylation of H3(Ser¹⁰), and showed diminished binding of NF-B RelA/p65 to the TNF promoter. Similar levels of NF-B p50 occurred at the TNF promoter in the basal state, during active transcription, and in the silenced phenotype. RelB, which acts as a repressor of TNF 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.

Received for publication, June 4, 2007 , and in revised form, July 18, 2007.

^* 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.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. Tel.: 336-716-8622; Fax: 336-716-1214; E-mail: melgazza{at}wfubmc.edu.

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