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Glucocorticoid Regulation of 24-Hour Oscillation in Interferon Receptor Gene Expression in Mouse Liver

Pharmaceutics (S.K., N.M., S.O.) and Clinical Pharmacokinetics (H.S., S.H.), Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Biochemistry (Y.K., S.S., H.S.), Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan; and Department of Hospital Pharmacy (H.T.), Faculty of Medicine, Tottori University, Yonago 683-8504, Japan

Address all correspondence and requests for reprints to: Shigehiro Ohdo, Ph.D., Professor, Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan. E-mail: ohdo{at}phar.kyushu-u.ac.jp.

Although the antiviral effect of interferon (IFN) varies depending on 24-h oscillation in the expression of its specific receptor, the mechanism of oscillation remains to be clarified. Here we report that oscillation in the expression of the IFN receptor gene (IFN-/ß R1) in mouse liver is caused by the endogenous rhythm of glucocorticoid secretion. Brief exposure of mouse hepatic cells (Hepa 1–6) to corticosterone (CORT) resulted in a significant decrease in mRNA levels of IFN-/ß R1. The CORT-induced decrease in IFN-/ß R1 mRNA levels was reversed by pretreating the cells with RU486, a glucocorticoid receptor antagonist. The mRNA levels of IFN-/ß R1 gene in the liver of adrenalectomized mice were consistently increased throughout the day. However, a single administration of CORT to adrenalectomized mice significantly decreased the mRNA levels of IFN-/ß R1 in the liver. Furthermore, the rhythmic phase of IFN-/ß R1 expression was modulated after the alteration of rhythmicity in glucocorticoid secretion, which was induced by restricted daily feeding. As a consequence, under manipulation of the feeding schedule, 2'-5' oligoadenylate synthase activities, as an index of antiviral effect, in plasma and liver at 24 h after IFN- injection also varied depending on the alteration of glucocorticoid secretion rhythm. These results suggest that the endogenous rhythm of glucocorticoid secretion is involved in the circadian regulation of IFN-/ß R1 expression in mouse liver. Our findings also support the notion that monitoring the 24-h variation in IFN receptor function is useful for selecting the most appropriate time of day to administer IFN.