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Differential Effects of Interleukin-1β, Interleukin-2, and Interferon-γ on the Inducible Expression of CYP 1A1 and CYP 1A2 in Cultured Rabbit Hepatocytes

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Abstract

The effects of interleukin-1β, interleukin-2 and interferon-γ and their combinations were investigated on induced cytochrome P 4501A of cultured rabbit hepatocytes considered 72 h after plating. Without apparent cellular toxicity, these cytokines provoke a significant decrease in TBZ- and BNF-induced P4501A1/2 expression. However specific patterns of action are revealed : IL-1β is the most potent cytokine in regard to CYP1A1/2 mRNA suppression whereas IL-2 exerts repressive effects only on P4501A1 induced expression. Although being a strong inhibitor of induced enzymatic activities and protein contents, IFN-γ exhibits only a weak influence on CYP1A1/2 mRNAs with the exception of its association with interleukins. All these results suggest that IL-1β and IL-2 promote mainly a transcriptional repression mechanism whereas IFN-γ would stimulate a post-transcriptional suppressive pathway.

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    In agreement, cooperative enhancement of the endogenous AhRR mRNA expression was actually observed in HeLa cells treated with 3MC and TPA (Fig.6 b). Finally, several cytokines such as interleukin-1β, tumor necrosis factor, and interferon-γ are reported to inhibit induced expression of CYP1A1 and CYP1A2 genes (33, 34). Since NF-κB is known to work as a downstream effector of these cytokines (35), the inhibitions of cytochrome P450 induction could be explained through the enhanced synthesis of AhRR by NF-κB.

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IL-1β, interleukin-1βIL-2, interleukin-2; IFN-γ, interferon-γ; P450, cytochrome P450; CYP1A1, gene encoding for P4501A1 isoenzyme; TBZ, thiabendazole; BNF, β-naphtoflavone; EROD, ethoxyresorufin O-deethylase; MROD, methoxyresorufin O-demethylase; LDH, lactate dehydrogenase; DMSO, dimethylsulfoxide; GAPDH, glyceraldehyde phosphate dehydrogenase; FCS, fetal calf serum; SDS-PAGE, sodium dodecylsulfate-polyacrylamide gel electrophoresis;

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To whom correspondence should be addressed. Fax : 33 (0) 561 28 53 10. E-mail : pgaltier @ toulouse.inra.fr.

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