Dosing schedule-dependent change in the disruptive effects of interferon-alpha 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-alpha 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-alpha on the intrinsic biological rhythms in mice by comparing two dosing schedules, continuous administration and repetitive injection. Continuous administration of IFN-alpha 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-alpha. These results indicate that treatment with IFN-alpha does not always modulate the circadian clock function. This notion was also supported by in vitro findings that the inhibitory action of IFN-alpha on the expression of clock genes was dependent on its exposure time to cells. The alteration of clock function induced by IFN-alpha could be avoided by optimizing the dosing schedule.
Shinohara
Akiko
A
Department of Medico-Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Koyanagi
Satoru
S
Hamdan
Ahmed Mohsen
AM
Matsunaga
Naoya
N
Aramaki
Hironori
H
Ohdo
Shigehiro
S
D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002940:Circadian Rhythm / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D007958:Leukocyte Count; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D056950:Period Circadian Proteins; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism
D018797:Cell Cycle Proteins; D016898:Interferon-alpha; D009687:Nuclear Proteins; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D012313:RNA; D003345:Corticosterone