Mechanism of Suppression of Cytochrome P-450 1A1 Expression by Tumor Necrosis Factor-α and Lipopolysaccharide

• Published in: The Journal of biological chemistry 2001-10, Vol.276 (43), p.39638-39644
• Main Authors: Ke, Sui, Rabson, Arnold B., Germino, J.F., Gallo, Michael A., Tian, Yanan
• Format: Article
• Language: English
• Subjects: Acetylation; aryl hydrocarbon receptors; Chromatin - metabolism; chromatin remodeling; cyp1a1 gene; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A1 - genetics; Gene Expression Regulation, Enzymologic - drug effects; Genes, Reporter; Histone Acetyltransferases; Histones - metabolism; Ligases - biosynthesis; Ligases - genetics; lipopolysaccharides; Lipopolysaccharides - pharmacology; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Nuclear Proteins - metabolism; Nuclear Receptor Coactivator 1; Promoter Regions, Genetic; pyrrolidine dithiocarbamate; Pyrrolidines - pharmacology; Receptor Cross-Talk; Receptors, Aryl Hydrocarbon - metabolism; Signal Transduction; Thiocarbamates - pharmacology; Trans-Activators - metabolism; Transcription Factors - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M106286200

Proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin-1β, and lipopolysaccharides (LPS), suppress the gene expression of cytochrome P-450 1A1 (cyp1a1). The mechanism of the suppression is not well understood. In present study, we show that activation of nuclear factor-κB (NF-κB) is a critical event leading to the suppression ofcyp1a1 gene expression, thus providing an underlying mechanism for the TNF-α- and LPS-induced cyp1a1suppression. We demonstrated that: (i) inducible RelA expression down-regulated aryl hydrocarbon receptor (AhR) activated reporter gene; (ii) the suppressive effects of LPS and TNF-α on the AhR-activated reporter gene could be blocked by pyrrolidine dithiocarbamate, which is known to inhibit NF-κB action; and (iii) TNF-α and LPS-imposed repression could be reversed by the NF-κB super repressor (SRIκBα), thus demonstrating the specific involvement of NF-κB. Furthermore, nuclear receptor coactivators p300/CBP and steroid receptor coactivator-1 act individually as well as cooperatively to reverse the suppressive effects by NF-κB on the AhR-activated reporter gene, suggesting that these transcriptional coactivators serve as the common integrators for the two pathways, thereby mediating the cross-interactions between AhR and NF-κB. Finally, using the chromatin immunoprecipitation assay, we demonstrated that AhR ligand induces histone H4 acetylation at the cyp1a1promoter region containing the TATA box, whereas TNF-α inhibits this acetylation, suggesting that AhR/NF-κB interaction converges at level of transcription involving chromatin remodeling.