The interleukin-2 receptor down-regulates the expression of cytochrome P450 in cultured rat hepatocytes.
OBJECTIVE
Interleukin (IL) 2 is used in advanced cancers, but its effects on cytochrome P450 remain unknown. Other cytokines down-regulate hepatic cytochrome P450, but it is not known whether this involves cytokine receptors. The aim of this study was to determine whether the IL-2 receptor is expressed on hepatocytes and whether its activation by IL-2 depresses cytochrome P450 in cultured rat hepatocytes.


METHODS
A monoclonal antibody specific for the rat IL-2 receptor alpha chain was used to label the receptor, whereas effects on cytochrome P450 were determined after 24 hours of culture with human recombinant IL-2 (5000 U/mL).


RESULTS
The presence of the IL-2 receptor in hepatocytes was shown by immunoblots, flow cytometry, and scanning confocal microscopy. 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 cytochrome 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 cultured rat hepatocytes by interacting with its receptor expressed on hepatocytes.
Tinel
M
M
INSERM Unité 24, Hôpital Beaujon, Clichy, France.
Robin
M A
MA
Doostzadeh
J
J
Maratrat
M
M
Ballet
F
F
Fardel
N
N
el Kahwaji
J
J
Beaune
P
P
Daujat
M
M
Labbe
G
G
D000818:Animals; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015536:Down-Regulation; D005434:Flow Cytometry; D019833:Genistein; D006801:Humans; D015151:Immunoblotting; D007376:Interleukin-2 / Q000235:genetics / Q000502:physiology; D007529:Isoflavones / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015375:Receptors, Interleukin-2 / Q000502:physiology*
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D007529:Isoflavones; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein; D011505:Protein-Tyrosine Kinases