Alteration of intrinsic biological rhythms during interferon treatment and its possible mechanism.
One of the most indispensable biological functions for all living organisms is the circadian clock, which acts like a multifunctional timer to regulate the homeostatic system, including sleep and wakefulness, hormonal secretions, and various other bodily functions with a 24-h cycle. We reported previously that interferon (IFN) has the ability to modulate the biological clock system at the genetic level. In the present study, this mechanism was investigated further by evaluating the effects of IFN-alpha on circadian output function. Treatment of cultured hepatic cells (HepG2) with IFN-alpha significantly decreased the protein levels of CLOCK and BMAL1, which are positive regulators of circadian output rhythm, then their mRNA levels. Aurintricarboxylic acid, a ligand inhibitor of IFN-alpha, dose dependently inhibited the IFN-alpha-induced phosphorylation of the signal transducer and activator of transcription 1 (STAT1) protein in HepG2 cells, accompanied by the restoration of Clock and Bmal1 mRNA levels. The continuous administration of IFN-alpha significantly decreased CLOCK and BMAL1 protein levels in the suprachiasmatic nucleus and liver of mice, thereby preventing oscillations in the expression of clock and clock-controlled output genes. These results reveal a possible pharmacological action by IFN-alpha on the core circadian oscillation mechanism and indicate that the disruptive effect of IFN-alpha on circadian output function is the underlying cause of its adverse effects on 24-h rhythms in physiology and behavior.
Koyanagi
Satoru
S
Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Ohdo
Shigehiro
S
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D001683:Biological Clocks / Q000187:drug effects* / Q000502:physiology; D056926:CLOCK Proteins; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D016898:Interferon-alpha; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C538943:CLOCK protein, human; C538944:Clock protein, mouse