TRANSFORMING GROWTH-FACTOR-BETA-1 DOWN-REGULATES BASAL AND POLYCYCLICAROMATIC HYDROCARBON-INDUCED CYTOCHROMES P-450 1A1 AND 1A2 IN ADULT HUMAN HEPATOCYTES IN PRIMARY CULTURE

The effects of interleukin (IL)-1 beta, IL-4, IL-6, tumor necrosis fac tor (TNF)-alpha, interferon (IFN)-alpha, IFN-gamma, and transforming g rowth factor (TGF)-beta 1 on cytochrome P-450 (CYP)1A expression and p olycyclic aromatic hydrocarbon (PAH)-mediated induction in primary hum an hepatocyte cultures were determined. Most cytokines that were previ ously found to decrease basal CYP expression could counteract PAH indu ction of CYP1A mRNA and its associated ethoxyresorufin-O-deethylation (EROD) activity. IL-1 beta and TNF-alpha blocked 3-methylcholanthrene (3-MC)-induced EROD activity by up to 25 and 44%, respectively. IFN-al pha and IFN-gamma antagonized EROD induction by up to 61 and 70%, resp ectively. TGF-beta 1 proved to be the most effective cytokine, because 72 hr of treatment with 2 ng/ml TGF-beta 1 produced nearly 100% inhib ition of 3-MC- and benzo(a)pyrene-induced CYP1A1 and CYP1A2 mRNAs and EROD activity. Treatment with cycloheximide in combination with 3-MC l ed to superinduction of CYP1A mRNA, under which conditions TGF-beta 1 did not block induction, suggesting the requirement for protein synthe sis for the suppressive effect of the cytokine. In addition, TGF-beta 1 augmented AP-1-binding activity, suggesting that fos and/or jun prot ooncogene products could be implicated in the response. Our results de monstrate that IL-1 beta, TNF-alpha, and IFNs antagonized PAH-mediated induction of CYP1A gene expression in human hepatocytes. In addition, we report the finding of a novel effect of TGF-beta 1, which was able to prevent CYP1A1 and -1A2 induction by two different PAHs.