Interleukin-2 Overexpresses c-myc and Down-Regulates Cytochrome P-450 in Rat Hepatocytes

The interaction of interleukin-2 (IL-2) with its receptor (IL-2R) decreases cytochrome P-450 (CYP) expression in rat hepatocytes. Because IL-2 increases c-Myc in lymphocytes and because c- myc overexpression represses several genes, we postulated that the IL-2/IL-2R interaction may increase c-Myc and thereby down-regulate CYP in hepatocytes. Cultured rat hepatocytes were exposed for 24 h to IL-2 (350 U/ml) and other agents. IL-2 increased c- myc mRNA and protein but decreased total CYP and the mRNAs and proteins of CYP2C11 and CYP3A. The IL-2-mediated c- myc overexpression and CYP down-regulation were prevented by 1) genistein (a tyrosine kinase inhibitor that blocks the initial transduction of the IL-2R signal), 2) retinoic acid, butyric acid, or dimethyl sulfoxide (three agents that block c- myc transcription), or 3) an antisense c- myc oligonucleotide (which may cause rapid degradation of the c- myc transcript). It is concluded that IL-2 causes the overexpression of c- myc and the down-regulation of CYPs in rat hepatocytes. Block of c- myc overexpression, at three different levels with five different agents, prevents CYP down-regulation, suggesting that c- myc overexpression may directly or indirectly repress CYP in hepatocytes.