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, inter leukin-1 beta, and lipopolysaccharides (LPS), suppress the gene expression of cytochrome P-450 1A1 (cyp1a1). The mechanism of the suppression is not w ell understood. In present study, we show that activation of nuclear factor -kappaB (NF-kappaB) is a critical event leading to the suppression of cyp1a 1 gene expression, thus providing an underlying mechanism for the TNF-alpha - and LPS-induced cyp1a1 suppression. We demonstrated that: W inducible Re1 A expression down-regulated aryl hydrocarbon receptor (AhR) activated repor ter gene; (ii) the suppressive effects of LPS and TNF-alpha on the AhR-acti vated reporter gene could be blocked by pyrrolidine dithiocarbamate, which is known to inhibit NF-kappaB action; and (iii) TNF-alpha and LPS-imposed r epression could be reversed by the NF-kappaB super repressor (SRI kappaB al pha), 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 effec ts by NF-kappaB on the AhR-activated reporter gene, suggesting that these t ranscriptional coactivators serve as the common integrators for the two pat hways, thereby mediating the cross-interactions between AhR and NF-kappaB. Finally, using the chromatin immunoprecipitation assay, we demonstrated tha t AhR ligand induces histone H4 acetylation at the cypla1 promoter region c ontaining the TATA box, whereas TNF-alpha inhibits this acetylation, sugges ting that AhR/NF-kappaB interaction converges at level of transcription inv olving chromatin remodeling.