RelB Sustains IκBα Expression during Endotoxin Tolerance

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-1 beta (IL-1 beta) 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-1 beta 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.