Abstract
BackgroundAlthough the number of circulating immune cells is subject to high-amplitude circadian rhythms, the underlying mechanisms are not fully understood.MethodsTo determine whether intact CLOCK protein is required for the circadian changes in peripheral blood cells, we examined circulating white (WBC) and red (RBC) blood cells in homozygous Clock mutant mice.ResultsDaytime increases in total WBC and lymphocytes were suppressed and slightly phase-delayed along with plasma corticosterone levels in Clock mutant mice. The peak RBC rhythm was significantly reduced and phase-advanced in the Clock mutants. Anatomical examination revealed hemoglobin-rich, swollen red spleens in Clock mutant mice, suggesting RBC accumulation.ConclusionOur results suggest that endogenous clock-regulated circadian corticosterone secretion from the adrenal gland is involved in the effect of a Clock mutation on daily profiles of circulating WBC. However, intact CLOCK seems unnecessary for generating the rhythm of corticosterone secretion in mice. Our results also suggest that CLOCK is involved in discharge of RBC from the spleen.
Highlights
The number of circulating immune cells is subject to high-amplitude circadian rhythms, the underlying mechanisms are not fully understood
Mutant CLOCK protein can still form heterodimers with BMAL1 that binds to DNA, but these are deficient in transcriptional activity [9,10]
To determine whether intact CLOCK protein is required for the circadian changes in peripheral blood cells, we examined circulating white blood cells (WBC) and red blood cells (RBC) and evaluated plasma levels of corticosterone (CS) in homozygous Clock mutant mice
Summary
The number of circulating immune cells is subject to high-amplitude circadian rhythms, the underlying mechanisms are not fully understood. The number of circulating white blood cells (WBC) involved in immune defense is subject to high-amplitude circadian rhythms [1,2]. Periodic changes in the number of leukocytes circulating in the peripheral blood might result from several factors. The Clock gene encodes a basic helix-loop-helix (bHLH)-PAS transcription factor that plays an important role in the negative feedback loop of the circadian clock [9,10]. Like other bHLH transcription factors, CLOCK binds DNA and modulates transcription following dimerization. Mutant CLOCK protein can still form heterodimers with BMAL1 (a bHLHPAS transcription factor) that binds to DNA, but these are deficient in transcriptional activity [9,10]. CLOCK protein is involved in the transcriptional regulation of several circadian output genes as well as in the core circadian clock [11,12]
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