Mechanism of suppression of cytochrome P-450 1A1 expression by tumor necrosis factor-alpha and lipopolysaccharide.
Proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin-1beta, 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-kappaB (NF-kappaB) is a critical event leading to the suppression of cyp1a1 gene expression, thus providing an underlying mechanism for the TNF-alpha- and LPS-induced cyp1a1 suppression. We demonstrated that: (i) inducible RelA expression down-regulated aryl hydrocarbon receptor (AhR) activated reporter gene; (ii) the suppressive effects of LPS and TNF-alpha on the AhR-activated reporter gene could be blocked by pyrrolidine dithiocarbamate, which is known to inhibit NF-kappaB action; and (iii) TNF-alpha and LPS-imposed repression could be reversed by the NF-kappaB super repressor (SRIkappaBalpha), thus demonstrating the specific involvement of NF-kappaB. Furthermore, nuclear receptor coactivators p300/CBP and steroid receptor coactivator-1 act individually as well as cooperatively to reverse the suppressive effects by NF-kappaB 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-kappaB. Finally, using the chromatin immunoprecipitation assay, we demonstrated that AhR ligand induces histone H4 acetylation at the cyp1a1 promoter region containing the TATA box, whereas TNF-alpha inhibits this acetylation, suggesting that AhR/NF-kappaB interaction converges at level of transcription involving chromatin remodeling.
Ke
S
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Department of Environmental and Community Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Rabson
A B
AB
Germino
J F
JF
Gallo
M A
MA
Tian
Y
Y
D000107:Acetylation; D002843:Chromatin / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D008025:Ligases / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D011401:Promoter Regions, Genetic; D011759:Pyrrolidines / Q000494:pharmacology; D020239:Receptor Cross-Talk; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002843:Chromatin; D006657:Histones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009687:Nuclear Proteins; D011759:Pyrrolidines; D018336:Receptors, Aryl Hydrocarbon; D013859:Thiocarbamates; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; D019363:Cytochrome P-450 CYP1A1; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases