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

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-alpha/beta 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-alpha/beta R1. The CORT-induced decrease in IFN-alpha/beta R1 mRNA levels was reversed by pretreating the cells with RU486, a glucocorticoid receptor antagonist. The mRNA levels of IFN-alpha/beta 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-alpha/beta R1 in the liver. Furthermore, the rhythmic phase of IFN-alpha/beta 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-alpha 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-alpha/beta 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.