BCL-3 and NF-κB p50 Attenuate Lipopolysaccharide-induced Inflammatory Responses in Macrophages

• Published in: The Journal of biological chemistry Vol. 279; no. 48; pp. 49995 - 50003
• Main Authors: Wessells, Jennifer, Baer, Mark, Young, Howard A., Claudio, Estefania, Brown, Keith, Siebenlist, Ulrich, Johnson, Peter F.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 26.11.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M404246200

Lipopolysaccharide (LPS) induces expression of tumor necrosis factor α (TNFα) and other pro-inflammatory cytokines in macrophages. Following its induction, TNFα gene transcription is rapidly attenuated, in part due to the accumulation of NF-κB p50 homodimers that bind to three κB sites in the TNFα promoter. Here we have investigated the inhibitory role of BCL-3, an IκB-like protein that interacts exclusively with p50 and p52 homodimers. BCL-3 was induced by LPS with delayed kinetics and was associated with p50 in the nucleus. Forced expression of BCL-3 suppressed LPS-induced transcription from the TNFα promoter and inhibited two artificial promoters composed of TNFακB sites that preferentially bind p50 dimers. BCL-3-mediated repression was reversed by trichostatin A and was enhanced by overexpression of HDAC-1, indicating that transcriptional attenuation involves recruitment of histone deacetylase. Analysis of macrophages from p50 and BCL-3 knock-out mice revealed that both transcription factors negatively regulate TNFα expression and that BCL-3 inhibits IL-1α and IL-1β. In contrast, induction of the anti-inflammatory cytokine IL-10 was reduced in BCL-3 null macrophages. BCL-3 was not required for the production of p50 homodimers but BCL-3 expression was severely diminished in p50-deficient cells. Together, these findings indicate that p50 and BCL-3 function as anti-inflammatory regulators in macrophages by attenuating transcription of pro-inflammatory cytokines and activating IL-10 expression.