THE INTERLEUKIN-2 RECEPTOR DOWN-REGULATES THE EXPRESSION OF CYTOCHROME-P450 IN CULTURED RAT HEPATOCYTES

Background & Aims: Interleukin (IL) 2 is used in advanced cancers, but its effects on cytochrome P450 remain unknown. Other cytokines down-r egulate hepatic cytochrome P450, but it is not known whether this invo lves cytokine receptors. The aim of this study was to determine whethe r the IL-2 receptor is expressed on hepatocytes and whether its activa tion by IL-2 depresses cytochrome P450 in cultured rat hepatocytes. Me thods: A monoclonal antibody specific for the rat IL-2 receptor alpha chain was used to label the receptor, whereas effects on cytochrome P4 50 were determined after 24 hours of culture with human recombinant IL -2 (5000 U/mL). Results: The presence of the IL-2 receptor in hepatocy tes was shown by immunoblots, flow cytometry, and scanning confocal mi croscopy. IL-2 caused a 46% decrease in total cytochrome P450; a 35%, 35%, 36%, 26%, and 56% decrease in immunoreactive cytochrome P4501A1, 2B, 2C11, 2D1, and 3A, respectively; and a marked decrease in cytochro me P4503A2 and 2C11 messenger RNAs. Addition to the culture medium of the anti-receptor antibody or the tyrosine kinase inhibitor genistein prevented the IL-2-mediated decrease in cytochrome P450. Conclusions: IL-2 down-regulates the expression of cytochrome P450 genes in culture d rat hepatocytes by interacting with its receptor expressed on hepato cytes.