Dosing schedule-dependent change in the disruptive effects of interferon-α on the circadian clock function

Altered homeostatic regulation, including the disturbance of circadian rhythms, is often observed in patients undergoing interferon (IFN) therapy. We reported previously that IFN-α has the ability to modulate the circadian clock function at the molecular level and that the alteration of clock function could be overcome by changing the dosing schedule. In this study, we investigated the influence of IFN-α on the intrinsic biological rhythms in mice by comparing two dosing schedules, continuous administration and repetitive injection. Continuous administration of IFN-α to mice decreased the rhythm amplitude of locomotor activity, body temperature, leukocyte counts, and plasma corticosterone levels. The treatment also suppressed the oscillation in the expression of clock genes in the liver. On the other hand, modulation effects were scarcely observed in mice treated with repetitive injection of IFN-α. These results indicate that treatment with IFN-α does not always modulate the circadian clock function. This notion was also supported by in vitro findings that the inhibitory action of IFN-α on the expression of clock genes was dependent on its exposure time to cells. The alteration of clock function induced by IFN-α could be avoided by optimizing the dosing schedule.