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.
Tinel
M
M
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.
Elkahwaji
J
J
Robin
M A
MA
Fardel
N
N
Descatoire
V
V
Haouzi
D
D
Berson
A
A
Pessayre
D
D
D000818:Animals; D015152:Blotting, Northern; D020148:Butyric Acid / Q000494:pharmacology; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011233:Precipitin Tests; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014212:Tretinoin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007376:Interleukin-2; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D020148:Butyric Acid; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein; D004121:Dimethyl Sulfoxide