BCL-3 and NF-κB p50 Attenuate Lipopolysaccharide-induced Inflammatory Responses in Macrophages
| Autor: | Howard A. Young, Jennifer Wessells, Estefania Claudio, Mark Baer, Ulrich Siebenlist, Keith Brown, Peter F. Johnson |
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| Rok vydání: | 2004 |
| Předmět: |
Lipopolysaccharides
medicine.medical_treatment Biology Biochemistry Mice B-Cell Lymphoma 3 Protein Proto-Oncogene Proteins medicine Animals Transcriptional attenuation Promoter Regions Genetic Molecular Biology Transcription factor Mice Knockout Tumor Necrosis Factor-alpha Macrophages NF-kappa B NF-kappa B p50 Subunit Promoter Cell Biology Molecular biology Interleukin-10 Trichostatin A Cytokine Gene Expression Regulation Tumor necrosis factor alpha Histone deacetylase Transcription Factors medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 279:49995-50003 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m404246200 |
| Popis: | Lipopolysaccharide (LPS) induces expression of tumor necrosis factor alpha (TNFalpha) and other pro-inflammatory cytokines in macrophages. Following its induction, TNFalpha gene transcription is rapidly attenuated, in part due to the accumulation of NF-kappaB p50 homodimers that bind to three kappaB sites in the TNFalpha promoter. Here we have investigated the inhibitory role of BCL-3, an IkappaB-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 TNFalpha promoter and inhibited two artificial promoters composed of TNFalphakappaB 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 TNFalpha expression and that BCL-3 inhibits IL-1alpha and IL-1beta. 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. |
| Databáze: | OpenAIRE |
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