The interleukin-2 receptor down-regulates the expression of cytochrome P450 in cultured rat hepatocytes

Tinel, Marina; Robin, Marie-Anne; Doostzadeh, Jaleh; Maratrat, Michel; Ballet, François; Fardel, Nicolas; Kahwaji, Johny El; Beaune, Philippe; Daujat, Martine; Labbe, Gilles; Pessayre, Dominique

doi:10.1016/0016-5085(95)90648-7

Cited by 60 publications

(33 citation statements)

References 47 publications

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“…Two clinical investigations have demonstrated decreased CYP3A protein content and activity (Piscitelli et al, 1998a) in cancer patients and HIV-infected patients treated with IL-2 infusions. In vitro studies using primary rat hepatocytes have demonstrated that IL-2 can suppress CYP3A activity within 24 h (Tinel et al, 1995), in part by direct binding of IL-2 to IL-2 receptors on the hepatocyte surface . In contrast, we have observed only transient suppression of CYP3A activity in studies with human hepatocytes (Kashuba et al, 2000), which suggests that more than one mechanism may be involved in IL-2's effects in human liver.…”

Section: Interleukin 2 (Il-2)mentioning

confidence: 99%

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Kupffer Cell-Mediated Il-2 Suppression of Cyp3a Activity in Human Hepatocytes

Sunman

Hawke²,

LeCluyse³

et al. 2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Interleukin (IL)-2 administration has been shown to decrease CYP3A enzyme activity in vivo. To determine whether IL-2 suppression of human hepatocyte CYP3A activity is direct or whether it is facilitated by the presence of Kupffer cells, primary human hepatocytes were cultured alone or cocultured with primary human Kupffer cells at physiologic hepatocyte/Kupffer cell ratios of 10:1 or 10:4. Using proinflammatory cytokines as positive controls, IL-1 (0.2-20 ng/ml) and IL-6 (2-200 ng/ml) exposure resulted in a 70 to 90% decrease in CYP3A activity after 72 h in hepatocyte cultures. In the hepatocyte/Kupffer cell cocultures, an 80% decrease in CYP3A activity was observed with IL-1 (2 ng/ml) or IL-6 (20 ng/ml), suggesting that direct suppressive effects of proinflammatory cytokines on hepatocyte CYP3A activity are not substantially altered by Kupffer cells. In contrast to the effects of these proinflammatory cytokines, no sustained suppression of CYP3A activity was observed with IL-2 (2-200 ng/ml) in hepatocyte cultures. However, in hepatocyte/Kupffer cell cocultures, a concentration-dependent 50 to 70% suppression of CYP3A activity was observed with IL-2 at 72 h. In summary, these data suggest that Kupffer cells are required to reconstitute the suppressive effects of IL-2 on CYP3A activity that are observed in vivo and that hepatocyte/Kupffer cell cocultures may provide a useful model for investigating mechanisms of CYP3A4 regulation by cytokines. Of particular relevance to certain hepatic diseases, these findings suggest potential mechanisms whereby cytokines released from infiltrating blood mononuclear cells might modulate intercellular signaling and controls on hepatocyte function by various cell types that reside in liver.

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Section: Interleukin 2 (Il-2)mentioning

confidence: 99%

“…First, as suggested by Tinel et al (1995), IL-2 may produce direct suppression of CYP3A by binding to an IL-2 receptor on hepatocytes resulting in the transient suppression of CYP3A activity. Second, the effects of IL-2 may be indirect, i.e., through effects on Kupffer cells.…”

Section: Cytokine Suppression Of Cyp3a In Hepatocyte Coculturesmentioning

confidence: 99%

Kupffer Cell-Mediated Il-2 Suppression of Cyp3a Activity in Human Hepatocytes

Sunman

Hawke²,

LeCluyse³

et al. 2004

Drug Metab Dispos

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“…It has been shown that tumor necrosis factor-␣ represses CYP1A1 via redox regulation of nuclear factor-1 (Morel and Barouki, 1998), whereas interleukin 2 down-regulates rat CYP2C11 and CYP3A2 expression via induction of the proto-oncogene c-myc (Tinel et al, 1995), and interleukin 1 inhibits CYP2C11 transcription via binding of nuclear factor-B to a low-affinity binding site in its promoter (Iber et al, 2000). Nuclear receptors have also been shown to be relevant factors for cytochrome P450 down-regulation, because decreased expression of PXR and CAR was observed after cytokine incubation (Pascussi et al, 2000).…”

Section: Downloaded Frommentioning

confidence: 99%

Transcriptional Regulation of the Human HepaticCYP3A4: Identification of a New Distal Enhancer Region Responsive to CCAAT/Enhancer-Binding Protein β Isoforms (Liver Activating Protein and Liver Inhibitory Protein)

Martínez-Jiménez¹,

Gómez-Lechón²,

Castell³

et al. 2005

Mol Pharmacol

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CCAAT/enhancer-binding proteins (C/EBPs) are key transcription factors involved in the constitutive expression of several cytochrome P450 genes in the liver. Their concentration and activity change in several pathophysiological conditions. For instance, during inflammation, released cytokines induce repressive C/EBP␤-liver inhibitory protein (LIP), which antagonizes constitutive C/EBP transactivators [C/EBP␣ and C/EBP␤-liver activating protein (LAP)], down-regulating genes such as CYP3A4. However, the mechanism by which hepatic C/EBP factors modulate transcription of the CYP3A4 gene is not known. To elucidate the mechanism of action, we cotransfected luciferase reporter vectors, containing 5Ј-flanking deletions of the CYP3A4 gene, along with expression vectors for C/EBP␤-LAP, C/EBP␤-LIP, and C/EBP␣, in hepatic (HepG2) and nonhepatic (HeLa) cells. Analysis of the Ϫ3557 to Ϫ6954 base pair (bp) region demonstrated the existence of a 288-bp sequence at Ϫ5.95 kilobases (kb), which showed maximal response to C/EBP␤-LAP (ϳ30-fold increase in HepG2 cells). Coexpression of LAP with increasing amounts of LIP reduced the activating effect by ϳ70%. Site-directed mutagenesis of predicted C/EBP␤ binding sites demonstrated the presence of four functional C/EBP␤-responsive motifs within this distal flanking region. Further experiments using chromatin immunoprecipitation proved the binding of endogenous C/EBP␤ to the Ϫ5.95-kilobase enhancer of the CYP3A4 gene in human hepatocytes. Expression of recombinant LAP and LIP by means of adenoviral vectors resulted in their binding to this region, which was followed by activation/repression of CYP3A4. Together, our results uncover a new distal enhancer site in the CYP3A4 gene where C/EBP␤-LAP binds and activates transcription, whereas the truncated form, C/EBP␤-LIP, antagonizes LAP activity and causes gene repression.

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“…Tumor necrosis factor-a is believed to repress CYP1A1 via redox regulation of nuclear factor 1 (Morel and Barouki 1998), IL-2 downregulates rat CYP2C11 and CYP3A2 expression, probably via induction of the protooncogene c-myc (Tinel et al 1999;Thummel et al 2001), IL-1 inhibits CYP2Cll transcription via binding of NF-KB to a low-affinity site in the promoter of the gene (Iber et al 2000). IL-6 inhibits CYP3A4 through the induction of C/EBP,B-LIP which competes with other constitutive C/EBP-activating factors such as C/EBPa.…”

Section: Inhibition Of Detoxification By Inflammatory Responsementioning

confidence: 99%