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Clinical and Vaccine Immunology, January 2009, p. 104-110, Vol. 16, No. 1
1071-412X/09/$08.00+0     doi:10.1128/CVI.00320-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

RelB Sustains I{kappa}B{alpha} Expression during Endotoxin Tolerance{triangledown}

Xiaoping Chen,1* Barbara K. Yoza,1,2 Mohamed El Gazzar,1 Jean Y. Q. Hu,1 Sue L. Cousart,1 and Charles E. McCall1

Department of Internal Medicine, Section of Molecular Medicine,1 Department of General Surgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 271572

Received 1 September 2008/ Returned for modification 17 October 2008/ Accepted 4 November 2008

Transcription factors and chromatin structural modifiers induce clinically relevant epigenetic modifications of blood leukocytes during severe systemic inflammation (SSI) in humans and animals. These changes affect genes with distinct functions, as exemplified by the silencing of a set of acute proinflammatory genes and the sustained expression of a group of antimicrobial and anti-inflammatory genes. This paradigm is closely mimicked in the THP-1 human promonocyte cell model of lipopolysaccharide (LPS) endotoxin tolerance. We previously reported that LPS-induced de novo expression of RelB is required for generating tolerance to interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-{alpha}) expression. RelB represses transcription by binding with heterochromatic protein 1 {alpha} (HP1{alpha}) to the proximal promoters of IL-1β and TNF-{alpha}. In contrast, we report herein that RelB is required for sustained expression of anti-inflammatory I{kappa}B{alpha} in LPS-tolerant THP-1 cells. RelB transcription activation requires binding to the I{kappa}B{alpha} proximal promoter along with NF-{kappa}B p50 and is associated with an apparent dimer exchange with p65. We also observed that RelB induced during human SSI binds to the I{kappa}B{alpha} proximal promoter of circulating leukocytes. We conclude that RelB functions as a dual transcription regulator during LPS tolerance and human SSI by activating and repressing innate immunity genes.

* Corresponding author. Mailing address: Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: (336) 716-4377. Fax: (336) 716-1214. E-mail: xchen{at}wfubmc.edu

{triangledown} Published ahead of print on 19 November 2008.

Clinical and Vaccine Immunology, January 2009, p. 104-110, Vol. 16, No. 1
1071-412X/09/$08.00+0     doi:10.1128/CVI.00320-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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