title: RelB sustains IkappaBalpha expression during endotoxin tolerance.
abstract: 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-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) expression. RelB represses transcription by binding with heterochromatic protein 1 alpha (HP1alpha) to the proximal promoters of IL-1beta and TNF-alpha. In contrast, we report herein that RelB is required for sustained expression of anti-inflammatory IkappaBalpha in LPS-tolerant THP-1 cells. RelB transcription activation requires binding to the IkappaBalpha proximal promoter along with NF-kappaB p50 and is associated with an apparent dimer exchange with p65. We also observed that RelB induced during human SSI binds to the IkappaBalpha 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.
authors.affiliation: Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. xchen@wfubmc.edu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Yoza
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Gazzar
authors.forename: Jean Y Q
authors.initials: JY
authors.lastname: Hu
authors.forename: Sue L
authors.initials: SL
authors.lastname: Cousart
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
mesh_terms: D002460:Cell Line; D000090266:Chromobox Protein Homolog 5; D004247:DNA / Q000378:metabolism; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis*; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051841:Transcription Factor RelB / Q000378:metabolism*
chemical_list: C000715594:CBX5 protein, human; D004731:Endotoxins; D020672:I-kappa B Proteins; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; C497593:RELB protein, human; D000090266:Chromobox Protein Homolog 5; D000072000:NF-KappaB Inhibitor alpha; D051841:Transcription Factor RelB; D004247:DNA