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 increas es 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 ex posed for 24 h to IL-2 (350 U/ml) and other agents. IL-2 increased c-myc mR NA and protein but decreased total CYP and the mRNAs and proteins of CYP2C1 1 and CYP3A. The IL-2-mediated c-myc overexpression and CYP down-regulation were prevented by 1) genistein (a tyrosine kinase inhibitor that blocks th e 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, prev ents CYP down-regulation, suggesting that c-myc overexpression may directly or indirectly repress CYP in hepatocytes.