Abstract
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.
Footnotes
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Send reprint requests to: Dr. Dominique Pessayre, M.D., INSERM U481, Hôpital Beaujon, 92118 Clichy, France. E-mailpessayre{at}bichat.inserm.fr
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↵1 This study was supported in part by The European Union Eurohepatox BIOMED 2 Program (contract BMH4-CT96-0658), the Program Hospitalier de recherche Clinique 95-96, and the Réseau Hépatox.
- Abbreviations:
- IL
- interleukin
- IL-2R
- interleukin-2 receptor
- CYP
- cytochrome P-450
- DMSO
- dimethyl sulfoxide
- P(S)ODN
- phosphorothioate oligodeoxynucleotide
- DOTAP
- N-[1-(2,3-dioleoyloxy)propyl)]-N,N,N-trimethylammonium methylsulfate
- ECL
- enhanced chemiluminescence
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- C/EBP
- CCAAT/enhancer binding protein
- Received July 31, 1998.
- Accepted December 3, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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