Alteration of intrinsic biological rhythms during interferon treatment and its possible mechanism
Alteration of intrinsic biological rhythms during interferon treatment and its possible mechanism
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DOI：
10.1124/mol.62.6.1393
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发表时间：
2002-12-01
影响因子：
3.6
通讯作者：
Ohdo, S
中科院分区：
文献类型：
--
作者：
Koyanagi, S;Ohdo, S
生物体最不可或缺的生物功能之一是生物钟，它就像一个多功能的定时器，以24小时为周期调节体内平衡系统，包括睡眠和清醒、荷尔蒙分泌和其他各种身体功能。我们以前曾报道过干扰素在基因水平上具有调节生物钟系统的能力。在本研究中，通过评估干扰素-α对昼夜节律输出功能的影响，进一步探讨了这一机制。培养的肝细胞(HepG2)经干扰素-α处理后，其昼夜输出节律正向调节因子Clock和BMAL1的蛋白水平显著降低，随后其mRNA水平显著降低。干扰素-α的配体抑制剂金曲酸呈剂量依赖性地抑制干扰素-α诱导的HepG2细胞信号转导和转录激活子1(STAT1)蛋白的磷酸化，同时恢复Clock和BMal1的mRNA水平。持续给予干扰素-α显著降低了小鼠视交叉上核和肝脏中Clock和BMAL1的蛋白水平，从而阻止了Clock和Clock控制的输出基因表达的振荡。这些结果揭示了干扰素-α对核心昼夜节律振荡机制的可能药理作用，并表明干扰素-α对昼夜节律输出功能的干扰作用是其对24小时生理和行为节律产生不利影响的根本原因。
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.