Alteration of Intrinsic Biological Rhythms during Interferon Treatment and Its Possible Mechanism

Abstract

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-␣ on circadian output function. Treatment of cultured hepatic cells (HepG2) with IFN-␣ 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-␣, dose dependently inhibited the IFN-␣-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-␣ 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-␣ on the core circadian oscillation mechanism and indicate that the disruptive effect of IFN-␣ on circadian output function is the underlying cause of its adverse effects on 24-h rhythms in physiology and behavior.

Circadian Rhythms in the CNS and Peripheral Clock Disorders: Chronopharmacological Findings on Antitumor Drugs

“…However, the mechanism has not been clarified from the viewpoint of the disruptive effect of the drug on the clock genes. Recently we clarify the disruptive effect of IFN-α on the rhythm of mPer genes mRNA expression in the SCN of mice (22,23). These findings are supported by the inhibitory effect of IFN-α on the mRNA expression of mClock and mBmal1, which are important factors in activating the transcription of mPers, vasopressin, and the mDbp gene showing specific output function from the SCN to the periphery (9).…”

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

“…1 In addition to its critical roles in host defense, IFN-a has also been demonstrated to have several central nervous system (CNS) effects ranging from increased neuronal excitabilities 2 and regulation of temperature, 3 circadian rhythm 4 and sleep 3 to ingestive behavior 5 and emotion. 6 Despite wide therapeutic application of IFN-a in chronic viral infections and in several types of malignancies, there is mounting evidence that IFN-a is associated with brain damage in several clinical conditions including HIV-associated dementia, 7 CNS lupus 8 and familial Aicardi-Goutieres syndrome.…”

24-Hour Oscillation of Mouse Methionine Aminopeptidase2, a Regulator of Tumor Progression, Is Regulated by Clock Gene Proteins

“…Namely, the CLOCK:BMAL1 heterodimer acts through an E-box enhancer to activate the transcription of vasopressin, albumin D-element-binding protein, and prokineticin2 mRNAs, thereby showing a specific circadian output function (20 -22). Several factors can cause alterations to the clock function leading to illness and altered homeostatic regulation (10,11). The functional significance of the mammalian peripheral clocks is still unknown.…”