Interleukin-2 Overexpresses c-myc and Down-Regulates Cytochrome P-450 in Rat Hepatocytes1
- Marina Tinel,
- Johny Elkahwaji,
- Marie Anne Robin,
- Nicolas Fardel,
- Veronique Descatoire,
- Delphine Haouzi,
- Alain Berson and
- Dominique Pessayre
- Institut National de la Santé et de la Recherche Médicale U481 and Centre de Recherche de l’Association Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, Clichy, France
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
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- Received July 31, 1998.
- Accepted December 3, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
