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.

[1]  D. P. King,et al.  Role of the CLOCK protein in the mammalian circadian mechanism. , 1998, Science.

[2]  Jon C. Cole,et al.  Chronic Jet Lag Produces Cognitive Deficits , 2000, The Journal of Neuroscience.

[3]  S. Yamaguchi,et al.  Role of DBP in the Circadian Oscillatory Mechanism , 2000, Molecular and Cellular Biology.

[4]  D C Holley,et al.  A review of human physiological and performance changes associated with desynchronosis of biological rhythms. , 1984, Aviation, space, and environmental medicine.

[5]  U. Schibler,et al.  CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP. , 2000, Genes & development.

[6]  G R Stark,et al.  Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. , 2000, The EMBO journal.

[7]  J. Walsh The interferons. , 1985, Medical laboratory sciences.

[8]  F. Conquet,et al.  Circadian Expression of the Steroid 15 α-Hydroxylase (Cyp2a4) and Coumarin 7-Hydroxylase (Cyp2a5) Genes in Mouse Liver Is Regulated by the PAR Leucine Zipper Transcription Factor DBP , 1999, Molecular and Cellular Biology.

[9]  Lily Yan,et al.  Light-Induced Resetting of a Mammalian Circadian Clock Is Associated with Rapid Induction of the mPer1 Transcript , 1997, Cell.

[10]  Steven M. Reppert,et al.  Differential Functions of mPer1, mPer2, and mPer3 in the SCN Circadian Clock , 2001, Neuron.

[11]  Michelle Y. Cheng,et al.  Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus , 2002, Nature.

[12]  K Kume,et al.  Interacting molecular loops in the mammalian circadian clock. , 2000, Science.

[13]  J. Darnell STATs and gene regulation. , 1997, Science.

[14]  Ueli Schibler,et al.  The Orphan Nuclear Receptor REVERB Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator of the hypothalamus , 2002 .

[15]  M. Ishikawa,et al.  Lysozyme localization in human gastric and duodenal epithelium , 1988, Cell and Tissue Research.

[16]  Masaaki Ikeda,et al.  Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2. , 2002, Biochemical and biophysical research communications.

[17]  Y Sakaki,et al.  Resetting central and peripheral circadian oscillators in transgenic rats. , 2000, Science.

[18]  L. Lopez-Molina,et al.  The Transcription Factor DBP Affects Circadian Sleep Consolidation and Rhythmic EEG Activity , 2000, The Journal of Neuroscience.

[19]  Shigenori Watanabe,et al.  Inhibition of Light- or Glutamate-Induced mPer1Expression Represses the Phase Shifts into the Mouse Circadian Locomotor and Suprachiasmatic Firing Rhythms , 1999, The Journal of Neuroscience.

[20]  W. Duncan,et al.  Circadian rhythms and the pharmacology of affective illness. , 1996, Pharmacology & therapeutics.

[21]  Ueli Schibler,et al.  The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior , 1997, The EMBO journal.

[22]  Gregor Eichele,et al.  A Differential Response of Two Putative Mammalian Circadian Regulators, mper1 and mper2, to Light , 1997, Cell.

[23]  E. Maywood,et al.  mCRY 1 and mCRY 2 Are Essential Components of the Negative Limb of the Circadian Clock Feedback Loop to coordinated circadian outputs , 1999 .

[24]  R. Moore,et al.  Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. , 1972, Brain research.

[25]  Kazuo Sato,et al.  Multitissue Circadian Expression of Rat periodHomolog (rPer2) mRNA Is Governed by the Mammalian Circadian Clock, the Suprachiasmatic Nucleus in the Brain* , 1998, The Journal of Biological Chemistry.

[26]  A. Kalsbeek,et al.  A Diurnal Rhythm of Stimulatory Input to the Hypothalamo–Pituitary–Adrenal System as Revealed by Timed Intrahypothalamic Administration of the Vasopressin V1Antagonist , 1996, The Journal of Neuroscience.

[27]  J. Darnell,et al.  Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[28]  N. Dafny,et al.  Does the immune system communicate with the central nervous system? Interferon modifies central nervous activity , 1985, Journal of Neuroimmunology.

[29]  John B. Hogenesch,et al.  Mop3 Is an Essential Component of the Master Circadian Pacemaker in Mammals , 2000, Cell.

[30]  J. P. Card,et al.  Localization of vasopressin-, vasoactive intestinal polypeptide-, peptide histidine isoleucine-and somatostatin-mRNA in rat suprachiasmatic nucleus , 1988, Cell and Tissue Research.

[31]  K. Zoon,et al.  Aurin tricarboxylic acid, the anti-AIDS compound, prevents the binding of interferon-alpha to its receptor. , 1990, Biochemical and Biophysical Research Communications - BBRC.

[32]  Mark J. Zylka,et al.  A Molecular Mechanism Regulating Rhythmic Output from the Suprachiasmatic Circadian Clock , 1999, Cell.

[33]  B. Williams,et al.  Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays , 1998 .

[34]  S. Baron,et al.  The interferons. Mechanisms of action and clinical applications. , 1991, JAMA.

[35]  S. Hisano,et al.  Neuronal associations in the rat suprachiasmatic nucleus demonstrated by immunoelectron microscopy , 1992, The Journal of comparative neurology.

[36]  Ueli Schibler,et al.  The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator , 2002, Cell.

[37]  H. Aramaki,et al.  Changing the dosing schedule minimizes the disruptive effects of interferon on clock function , 2001, Nature Medicine.