TY - JOUR T1 - Effect of Transforming Growth Factor-β<sub>1</sub> on Expression of Aryl Hydrocarbon Receptor and Genes of <em>Ah</em>Gene Battery: Clues for Independent Down-Regulation in A549 Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 703 LP - 710 DO - 10.1124/mol.51.5.703 VL - 51 IS - 5 AU - Olaf Döhr AU - Ralf Sinning AU - Christoph Vogel AU - Peter Münzel AU - Josef Abel Y1 - 1997/05/01 UR - http://molpharm.aspetjournals.org/content/51/5/703.abstract N2 - An inhibitory effect on both constitutive and inducible expression of cytochrome P450 isoenzymes has been shown for different cytokines and growth factors. We previously described an inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 mRNA and enzyme activity by transforming growth factor-β1 (TGF-β1) in human lung cancer A549 cells. In the present study, we report that not only TCDD-induced expression of CYP1A1 but also basal mRNA expression of CYP1A1, CYP1B1, and aryl hydrocarbon receptor (AHR) was down-regulated by TGF-β1 in cells not treated with TCDD. In contrast, mRNA expression of the AHR partner protein Arnt (aryl hydrocarbon receptor nuclear translocator) was not influenced. Furthermore, TCDD-induced expression of CYP1B1 and NMO-1 was inhibited, and the IC50 values of 5–10 pmTGF-β1 were in the same range as observed for inhibition of CYP1A1 and AHR mRNA expression. Transfection studies with a plasmid containing a luciferase reporter gene under control of two dioxin-responsive elements indicate an effect on AHR protein expression. Results of time-course studies revealed a parallel inhibition of AHR and CYP1 mRNA expression, indicating that TGF-β1 is a direct negative regulator of transcription of these genes. The treatment of cells with cycloheximide led to a superinduction of TCDD-induced CYP1A1 and CYP1B1 mRNA expression and abolished the inhibitory effect of TGF-β1 on basal as well as TCDD-induced CYP1 and AHR mRNA expression. TGF-β1seems not to influence the stability of AHR mRNA. The results suggest that TGF-β1 induces rapid transcription and translation of an as-yet-unknown negative regulatory factor or factors that may directly regulate expression of AHR and genes of Ah gene battery. ER -