A two-clock model of circadian timing in the immune system of mammals

Disponible en ligne sur www.sciencedirect.com

Pathologie Biologie 56 (2008) 286–291 http://france.elsevier.com/direct/PATBIO/

Biological actuality

A two-clock model of circadian timing in the immune system of mammals Un mode`le a` double horloge de chronome´trage circadien dans le syste`me immunitaire des mammife`res J. Berger Department of Clinical Sciences, Faculty of Health and Social Studies, University of South Bohemia, 37005 Ceske Budejovice, Czech Republic Received 13 June 2006; accepted 12 October 2007 Available online 4 March 2008

Abstract It has been confirmed that clock genes, as well as the pineal hormone, have a role in the hypothalamic suprachiasmatic nucleus, the circadian endogenous pacemaker. It seems that the peripheral clock genes in the cells of the immune system subtly control biorhythms; their seeming lack of impact only showing that they work well. Some biorhythms even seem to be independent of a light/dark circadian regime. This apparent conflict in the mammalian time structure can be resolved by a two-clocks control model involving: (a) the endogenous gene clock, which is dominant in the neural system and (b) the exogenous clock of the immune system. Interactions between these two clocks can explain both the frequently observed individual differences in circadian rhythms and the subtle role of the peripheral clock genes. The endogenous clock facilitates an alternation in the immune system which counters external attacks in daytime and induces repair and advancement by night. # 2007 Elsevier Masson SAS. All rights reserved. Résumé On a confirmé que des gènes d´horloge, ainsi que l´hormone pinéale, ont un rôle au niveau du noyau suprachiasmatique de l’hypothalamus, site du pacemaker circadien endogène. Il semble que les gènes périphériques d´horloge dans les cellules du système de l´immunité contrôlent subtilement les biorythmes, leur absence apparente de pouvoir seulement indique qu’elles travaillent bien. Quelques biorythmes paraissent même indépendants du régime circadien des altérations de la lumière et l´obscurité. Ce conflit apparent dans la structure temporale des mammifères peut être dénoué par un modéle à deux horloges comprenant: (a) l´horloge génique endogène qui est dominante dans le système nerveux et (b) l´horloge exogène dans le système immunitaire. Des interactions entre ces deux horloges peuvent éclairer des différences aux rythmes circadiennes des individus ainsi que le rôle des gènes périphériques. L´horloge endogène facilite des modifications du système immunitaire, ce qui élimine les attaques extérieurs pendant le jour et induit des réparations et l´avancement pendant la nuit. # 2007 Elsevier Masson SAS. All rights reserved. Keywords: Biorhythm; Regulation; Haemato-immune system; Melatonin; Endogenous synchronization Mots clés : Biorythme ; Régulation ; Système hémato-immunitaire ; Mélatonine ; Synchronisation endogène

1. Introduction Models based on the gene regulation of biorhythms were first developed in the sixties shortly after the discovery of the genetic code. More recent models based on large experimental data are different, but they again confirm the central role of

E-mail address: [email protected].

genes and the importance of a light/dark regime for circadian timing in many organisms, including mammals [1,2]. Circadian rhythms seem to be the result of the expression of the so-called ‘clock genes’ and their synchronization by environmental and endogenous factors; mostly by light. Numerous clock genes have been identified in various organisms [3] (see for review). Circadian time is driven by daylight via melanopsin, which is a photoreactive pigment in the retina; retinal ganglion cells project glutamatergic and

0369-8114/$ – see front matter # 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.patbio.2007.10.001

J. Berger / Pathologie Biologie 56 (2008) 286–291

287

PACAP-immunoreactive fibres onto the core of the hypothalamic suprachiasmatic nucleus (SCN) via the retinohypothalamic tract. Glutamate receptors thus activated trigger a Ca2+ influx and CREB/mitogen activating protein kinase phosphorylation pathway, which starts a per gene expression [4]. The generation of internal clock time occurs in the hypothalamic suprachiasmatic nucleus and these oscillations spread throughout the brain and to the peripheral organs which contain peripheral clocks [5]. In this paper, we discuss why a number of observations are unexplained, and that some rhythms need not be synchronized by a light/dark regime influencing clock gene expression. Against this background, we suggest a new model for the regulation of circadian rhythms in mammals. 2. The endogenous neural clock The circadian clock, situated in the SCN, controls the release of norepinephrine from the dense pineal sympathetic afferents. Norepinephrine has a pivotal role in the nocturnal stimulation of melatonin synthesis, but the presence of numerous other transmitters originating from various other sources has been also reported in the pineal gland [6]. Modulation by melatonin of glutamatergic transmission from cones to horizontal cells is thought to be in part responsible for circadian changes in the light responsiveness of cone horizontal cells in the carp teleost retina [7]. The pineal gland synthesises hormone melatonin at high levels at night and is therefore, dubbed the ‘hormone of darkness’. Findings that cells from the SCN also express melatonin receptors [8] show that there is some feedback between the SCN and the pineal gland cells. We assume that the SCN functions are also regulated by components of the immune system. Cells in the ventrolateral part of the SCN express the receptor for g interferon; the expression occurs in a circadian manner and is light-dependent [9]. Interferon-a disrupts photic induction of the per gene in the SCN [10]. The fact that SCN-regulations can also influence the circadian rhythms of some immunological characteristics is supported by findings that experimental destruction of the SCN markedly alters corticosterone concentration and consequently lymphocyte counts [11]. The circadian clock in the vertebrate retina regulates dopamine release by the activation of melatonin receptors [12]. There is no doubt that a light regime is very important for regulation of many biorhythms and it seems that the influence of light on mammal physiology is mediated by melatonin level rhythms. Why is the role of the regulation of rhythms in blood and haematopoietic cells so poorly understood? 3. The role of melatonin in haemato-immune cells Melatonin, which is synthesized in the pineal gland under the control of a clock gene in the SCN is an important synchronizer of circadian rhythms in the whole body, and also has an immuno-haematopoietic role (Fig. 1). Many papers show the various effects of melatonin in blood and haematopoietic cells, including modulation of the T helper cell (Th) and NK

Fig. 1. Role of melatonin in immune cells; mt: melatonin.

activity, thymus cellularity, leucocyte and lymphocyte counts, interleukine, IL-2, IL-6, IL-12, and IFN-g production, etc. [13]. Melatonin alone does not affect lymphocyte proliferation, but does potentiate the corticosteroidal inhibition of lymphocyte proliferation [14]. Melatonin inhibits the programmed cell death of immune cells, presumably through the regulation of Bax protein levels [15]. Inhibition of pineal melatonin synthesis by the administration of propranolol in the evening, results in immunosuppression (i.e., depression of the primary antibody response to sheep red blood cells, and spleen cells from the subject mice showed a reduced reactivity against antigens in the autologous mixed lymphocyte reaction); an evening injection of melatonin reverses previously depressed reactivity against antigens in the above-mentioned lymphocyte reaction. Melatonin is also able to antagonize the depression of antibody production induced by corticosterone [16]. It has been documented that immune cells can carry melatonin receptors and activation of these receptors, for example, in T helper cells enhances the reading of g-interferon, IL-2 and opioid cytokines which can react with IL-4 and dynorphin-B. Opioid cytokines influence haematopoiesis through receptors in stromal bone marrow cells. g-interferon and colony simulating factors may also modulate melatonin production in the pineal gland [17]. Melatonin counteracts the inhibitory effect of prostanglandin E2 on IL-2 production in lymphocytes, via its mt1 membrane

288

J. Berger / Pathologie Biologie 56 (2008) 286–291

receptor [18]. Melatonin G-protein coupled receptors are in the target tissues [19]; these receptors have been found among others in both the membrane and nuclei of immune cells. Melatonin receptors regulate several second messengers such as cAMP, cGMP, diacylglycerol, inositol triphosphate, arachidonic acid, and intracellular Ca2+ concentration; melatonin can regulate distinct second messengers and even regulate positively or negatively the same signal transduction pathway [20]. Activation of a mt2 melatonin receptor enhances splenocyte proliferation and inhibits leucocyte rolling in the microvasculature, while activation of a mt3 receptor inhibits leukotriene B4-induced leucocyte adhesion [21]. RORb receptors are expressed in the retina, pineal gland and SCN, [22], but their role in the regulation of rhythms is not understood. Although we have mentioned above that melatonin alone does not regulate the circadian rhythms of circulating leucocytes, it is possible that an opposite influence of activated immune cells on the pineal gland is possible [13]. Moreover, the circadian rhythm of melatonin can modulate the mental state [23] which is interconnected with the immune system through neuroimmune processes. The corticotropic axis seems to be an example of an important synchronizer of haemato-immune rhythms [24], but psychophysiological processes construct a complicated system which does not reflect either endogenous or exogenous light dependent simple effects. The findings mentioned above show that the regulation of circadian rhythms is correlated with the modulation of immunity by melatonin, but could it also be strongly regulated by exogenous stimuli, i.e., independent on the light-retina inputs described above? 4. Exogenous synchronization The fact that circadian rhythms in immune cells are mostly correlated to a light/dark regime and also react to exogenous stimuli is well-known [25,26]. In contrast to most of the abovementioned data, several papers have been published which show that light does not synchronise certain circadian rhythms. For example, special disorders are a cause of cyclical changes in peripheral blood cell counts [27], but they do not represent a normal regulation mechanism of biorhythms; these cyclic events are the consequence of a proliferation defect. Without doubt, many haemato-immune characteristics are synchronised in correlation with a light/dark regime [28], but data from studies on the regulation of biorhythms which document that the normal circadian rhythms were not synchronised by light, call for an explanation (Fig. 2). Circadian oscillations in haematopoietic stem cell counts do not seem to be an endogenous rhythm, as synchronous waves with this characteristic are a consequence of control in their cells’ proliferation [29]. Granulocytes and lymphocyte subsets (natural killer cells, extrathymic T cells, gdT cells, and CD8) with their maxima during daytime, carry a high density of adrenergic receptors, and lymphocyte subsets (T cells, B cells, abT cells, and CD4), while those with their peaks at night carry a high proportion of cholinergic receptors [30]. These data can explain the modification of circadian rhythms which are not in

Fig. 2. Two-clock model of the regulation of circadian rhythms. One main clock is set into the nerve system, it is synchronized by light/dark regime and it is endogenous. Other clock is set into the immune system, it is synchronised by environmental factors or changes in the organism metabolism and it is exogenous. Both clock interact through hormonal messengers. SCN: suprachiasmatic nucleus.

correlation with factors influencing the cell cycle of their proliferating precursors. Seasonal changes of circadian rhythms in circulating leucocytes and their types in rats under an artificial light/dark regime for 12 h/12 h, seem to be identical to changes in rats maintained under a natural light period (solstice: LD 8 h/16 h) [31]. These data suggested that a light/dark regime may not be necessary for synchronization of some haemato-immune circadian rhythms. Persistent T lymphocyte rhythms in rats under permanent light, observed by Depres-Brummer et al. [32], confirm previously mentioned observations that the immunological system can be independent of endogenous neural biorhythms. The size of human lymphocyte nucleoli is mostly higher in the morning than in the evening [33], but the position of the peak for different human subjects varies in a similar way to the variation in marrow DNA synthesis described by Smaaland et al. [34]. As there is a large literature on the circadian control of mammalian cell cycle kinetics [35] and the nucleolus is a major centre for cell cycle progression [36], we suggest that the rhythms in DNA synthesis and nucleolar size referred to, cohere. It seems ingenious that the morning peak represents the preparedness of the lymphocytes to increase the biosynthesis of immunoglobulins during the subjective day, with continuous activity and with possible immunostimulative attacks. However, the actual antibody requirement can be different and the circadian rhythm of nucleolar size can be very individual, as is usual for many exogenous biorhythms. As the circadian rhythms of nucleolar size in neurons are very uniform [37], the larger influence of exogenous stimuli via endogenous factors on the lymphocyte function could be the reason why circadian

J. Berger / Pathologie Biologie 56 (2008) 286–291

rhythms in lymphocyte nucleolar size [33] are more individual. Lymphocyte nucleoli, participators of the immunity system, seem to be able to respond rapidly at any time. 5. Internal synchronization of haemato-immune characteristics Various plasma components oscillate and their circadian changes can represent one of the synchronizers of leucocyte counts and functions. Prostaglandin E1 enhances the function of T suppressor lymphocytes which control overactive antibody-producing B lymphocytes [38], and rhythms in the level of prostaglandin can induce appropriate rhythms in the immune system. Higher levels of the well-known immunosuppressant cortisol may inhibit IL-2 synthesis and be responsible for lymphocyte migration into tissues [39,40]. Circadian rhythms in CD3 (T cells), CD4 (T helper/inducer), and CD8 (T suppressor/cytotoxic) counts are opposite to the rhythm in cortisol levels with a morning maximum; those in CD56 (natural killer cells) counts and NK cell activity are similar to the circadian rhythm in cortisol [41]. We do not know how to explain why the acrophase of lymphocyte subpopulations in the paper of both Kronfol et al. [41] and Suzuki et al. [30] is different compared to data published in several studies published by Mazzoccoli et al. [42], but this controversy does not weaken the already mentioned findings that plasma components influence cellular immunity; that is to say, circadian rhythms in plasma components can induce rhythms in other haemato-immune characteristics. We suppose that these differences could also be caused by various exogenous immune stimuli as with our findings on the rhythm in nucleolar size [33], and exogenous synchronization may be the most important factor for circadian rhythm in the count and function of white blood cells. 6. Synchronizers of peripheral oscillators Time of feeding is another potent synchronizer for peripheral oscillators [43] as well as periodicity in social contacts or stress [44] and, perhaps, thermoperiods in the environment of mammals. The evidence for social entrainment in men is from studies on the synchronization of circadian rhythms in a few totally blind patients. There may be many more similar synchronizers yet to be discovered. Moreover, visible light (400–700 nm) can penetrate epidermal and dermal layers of the skin and may directly interact with circulating lymphocytes to modulate the immune function. In vivo exposure to UV-B (280–320 nm) and UV-A (320– 400 nm) radiation, in contrast to visible light, can alter the normal human immune function only by a skin-mediated response [45]. It seems that it is not only periodic changes of immunostimulative impulses that induce rhythmic variations in leucocyte functions; the significance of the eventual modulation of immunity by direct effects on cells also needs to be verified. Although clock genes were discovered in immune and haematopoietic cells [46,47], their role in the biorhythms of

289

blood cells remains unclear and we cannot accept that they induce oscillations which are easily overlapped by other stimuli originating from both internal metabolic rhythms and environmental factors, such as light and immune impulses. The discovery of two chronotypes of clock gene expression patterns in human circulating mononuclears [48] could reflect the unrecognized complexity of clock gene regulation. The finding that CFU-GM counts also vary rhythmically in vitro, supports the idea that a circadian time-keeping system exists within these cells [49], but its influence on cellular timing is weak compared with the role of exogenous immune stimuli. Wehr et al. [50] pointed out that the human circadian system is similar to the Pittendrigh Daan model of the rodent circadian structure where two phases (one diurnal and one nocturnal) alternate. Thus, the above-mentioned findings support the hypothesis that circadian changes in leucocytes are exogenous. Their circadian changes seem to be induced more by periodicities in the environment and in blood cell production rather than by clock gene rhythmicity. This does not invalidate our model of circadian control because Wehr’s suggestion does not solve the problem of the almost opposite circadian rhythms in human synchronised subjects (see above). The Pittendrigh Daan twophase systems are present in both endogenous neural regulation and the exogenous haemato-immune clock. As in physics and chemistry, where pendulums beat in time a while after desynchronization, synchronization of peripheral clocks can be the result of a resonance. Internal noise can induce circadian oscillations when the corresponding deterministic system does not oscillate; this is internal noise stochastic resonance [51]. The coherence resonance phenomenon can be induced by internal noise, while the external noise can regulate the optimal system size [52]. Following this hypothesis, the apparent lack of impact of peripheral clocks only shows that they work well when they are successfully harmonized: when not, cancer can appear [53]. The absence for many years of any observation concerning the direct relationship between clock gene expression in the thalamus and the regulation of circadian rhythms in the haemato-immune system indicates that the haemato-immune system has its own circadian clock which is not regulated by the suprachiasmatic nucleus. This opinion is supported by Filipski et al. [54], who report that the destruction of suprachiasmatic nuclei in mice did not alter the phase distribution of their marrow cell cycle. 7. Conclusions Circadian rhythms in many characteristics of the immune system are well-documented and the role of the SCN, pineal gland and clock genes for the induction and regulation of mammalian circadian rhythms is important. However, there is no relation between clock gene expression in haematopoietic or blood cells and rhythms. Circadian rhythms in blood cell counts and functions seem to be exogenous as a consequence of interactions with many other oscillating characteristics in internal metabolism as well

290

J. Berger / Pathologie Biologie 56 (2008) 286–291

as in its external environment. The important role of exogenous stimuli for leucocyte functions can be the cause of individualized circadian rhythms. While the clock genes make possible the use of chronotherapies, the exogenous-immune clock entails individualized laboratory examinations before, and in the course of chronotherapy, to reach its highest efficiency. We suggest the two-clock timing model is the main controller of biorhythms in mammals. The genetic nature of endogenous circadian rhythms is expressed by the suprachiasmatic nucleus in the neural system, while an exogenous clock mechanism is mediated by the cell immunity system. As both main clocks – endogenous-neural and exogenous-immune – interact the mammal’s timing seems to be part of the general neuroimmune control plan. The model presented, with two pacemakers, is not a definitive model for the future: the exogenous part may contain different subsets potentially playing their own part. Acknowledgement This work was partially supported by the Ministry of Education CR grant 1274/06. References [1] Hastings MH, Herzog ED. Clock genes, oscillators, and cellular networks in the suprachiasmatic nuclei. J Biol Rhythms 2004;19:400–13. [2] Perreau-Lenz S, Pévet P, Buijs RM, Kalsbeek A. The biological clock: the bodyguard of temporal homeostasis. Chronobiol Int 2004;21:1–25. [3] Yamaguchi S, Isejima H, Matsuo T, Okura R, Yagita K, Kobayashi M, et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science 2003;302:1408–12. [4] Badiu C. Genetic clock of biologic rhythms. J Cell Mol Med 2003;7: 408–16. [5] Oishi K, Sakamoto K, Okada T, Nagase T, Ishida N. Humoral signals mediate the circadian expression of rat period homologue (rPer2) mRNA in peripheral tissues. Neurosci Lett 1998;256:117–9. [6] Simonneaux V, Ribelayga C. Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Pharmacol Rev 2003;55:325–95. [7] Huang H, Lee SC, Yang XL. Modulation by melatonin of glutamatergic synaptic transmission in the carp retina. J Physiol (London) 2005;569: 857–71. [8] River-Bermudez MA, Masana MI, Brown GM, Earnest DJ, Dubocovich M. Immortalized cells from the rat suprachiasmatic nucleus express functional melatonin receptors. Brain Res 2004;1002:21–7. [9] Lundkvist GB, Andersson A, Robertson B, Rottenberg ME, Kristensson K. Light-dependent regulation and postnatal development of the interferon-gamma receptor in the rat suprachiasmatic nuclei. Brain Res 1999; 849:231–4. [10] Ohdo S, Koyanagi S, Suyama H, Higuchi S, Aramaki H. Changing the dosing schedule minimizes the disruptive effects of interferon on clock function. Nat Med 2001;7:356–60. [11] Filipski E, King VM, Li X, Granda TG, Mormont MC, Liu XH, et al. Disruption of circadian coordination accelerates malignant growth in mice. Pathol Biol 2003;51:216–9. [12] Ribelayga C, Wang Y, Mangel SC. A circadian clock in the fish retina regulates dopamine release via activation of melatonin receptors. J Physiol (London) 2004;55:467–82. [13] Skwarlo-Sonta K, Majewski P, Markowska M, Oblap R, Olszanska B. Bidirectional communication between the pineal gland and the immune system. Can J Physiol Pharmacol 2003;81:342–9.

[14] Rogers N, van den Heuvel C, Dawson D. Effect of melatonin and corticosteroid on in vitro cellular immune function in humans. J Pineal Res 1997;22:75–80. [15] Hoijman E, Viegas LR, Keller Sarmiento MI, Rosenstein RE, Pecci A. Involvement of bax protein in the prevention of glucocorticoid-induced thymocytes apoptosis by melatonin. Endocrinology 2004;145:418–25. [16] Maestroni GJ, Conti A, Pierpaoli W. Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. J Neuroimmunol 1986;13:19–30. [17] Maestroni GJ, Conti A. The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties. J Neuroimmunol 1990;28: 167–76. [18] Carrillo-Vico A, Garcia-Maurino S, Calvo JR, Guerrero JM. Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor. FASEB J 2003;17:755–7. [19] von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res 2002;309: 151–62. [20] New DC, Tsim ST, Wong YH. G protein-linked effector and second messenger systems involved in melatonin signal transduction. Neurosignals 2003;12:59–70. [21] Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI. Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci 2003;8:D1093–108. [22] Jetten AM, Kurebayashi S, Ueda E. The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucl Acid Res Mol Biol 2001;69:205–47. [23] Kwiatkowski F, Lévi F. Chronobiologie et immunité. Pathol Biol 2005;53:251–4. [24] Kwiatkowski F, Abrial C, Gachon E, Chevrier R, Cure H, Chollet P. Stress, cancer et rythme circadien hythm de la mélatonine. Pathol Biol 2005;53:269–72. [25] Berger J. Chronohaematology. J Appl Biomed 2004;2:179–85. [26] Berger J. Current progress in chronohaematology. J Appl Biomed 2006;4:111–4. [27] Karimungi MG, Joshi BN. Diurnal sensitivity in melatonin-induced haematological changes in the male albino rat. Biol Signals 1996;5: 283–90. [28] Haus E, Smolensky MH. Biologic rhythms in the immune system. Chronobiol Int 1999;16:581–622. [29] Necas E, Znojil V. Non-circadian rhythm in proliferation of haematopoietic stem cells. Cell Tissue Kinet 1988;21:73–80. [30] Suzuki S, Toyabe S, Moroda T, Tada T, Tsukahara A, Iiai T, et al. Circadian rhythm of leucocytes and lymphocytes subsets and its possible correlation with the function of the autonomic nervous system. Clin Exp Immunol 1997;110:500–8. [31] Berger J. Seasonal influences on circadian rhythms in the blood picture of SPF rats housed under artificial illumination. Folia Haematol 1981;110:55–70. [32] Depres-Brummer P, Bourin P, Pages N, Metzger G, Levi F. Persistent T lymphocyte rhythms despite suppressed circadian clock outputs in rats. Am J Physiol 1997;273:R1891–9. [33] Berger Z, Berger J. Circadian rhythm of the lymphocyte nucleolar area. Comp Clin Pathol 2004;12:187–90. [34] Smaaland R, Sothern RB, Laerum OD, Abrahamsen JF. Rhythms in human bone marrow and blood cells. Chronobiol Int 2002;19:101–27. [35] Merrow M, Roenneberg T. Cellular clocks: coupled circadian and cell division cycles. Curr Biol 2004;14:R25–6. [36] Hernandez-Verdun D. The nucleolus: functional organization and assembly. J Appl Biomed 2004;2:57–69. [37] Seite R, Pébusque M-J. Chronobiological studies on the nucleolus. Chronobiol Int 1985;2:69–91. [38] Cunnane SC, Manku MS, Horrobin DF. The pineal and regulation of fibrosis: pinealectomy as a model of primary biliary cirrhosis: roles of melatonin and prostaglandins in fibrosis and regulation of T lymphocytes. Med Hypotheses 1979;5:403–14.

J. Berger / Pathologie Biologie 56 (2008) 286–291 [39] Milad MA, Ludwig EA, Anne S, Middleton Jr E, Jusko WJ. Pharmacodynamic model for joint exogenous and endogenous corticosteroid suppression of lymphocyte trafficking. J Pharmacokinet Biopharm 1994;22:469–80. [40] Palm S, Postler E, Hinrichsen H, Maier H, Zabel P, Kirch W. Twentyfour-hour analysis of lymphocyte subpopulations and cytokines in healthy subjects. Chronobiol Int 1996;13:423–34. [41] Kronfol Z, Nair M, Zhang Q, Hill EE, Brown MB. Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitaryadrenal axis hormones and sympathetic neurotransmitters. Psychosom Med 1997;59:42–50. [42] Mazzoccoli G, Grilli M, Carughi S, Puzzolante F, De Cata A, La Viola M, et al. Immune system alterations in lung cancer patients. Int J Immunopathol Pharmacol 2003;16:167–74. [43] Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M. Entrainment of the circadian clock in the liver by feeding. Science 2001;291:490–3. [44] Folkard S, Akestedt T. Trends in the risk of accidents and injuries and their implications for models of fatigue and performance. Aviat Space Environ Med 2004;75:A161–7. [45] Roberts JE. Light and immunomodulation. Ann NY Acad Sci 2000;917: 435–45. [46] Boivin DB, James FO, Wu AB, Cho-Park PF, Xiong HB, Sun ZS. Circadian clock genes oscillate in human peripheral blood mononuclear cells. Blood 2003;102:4143–5.

291

[47] Chen YG, Mantalaris A, Bourne P, Keng P, Wu JHD. Expression of mPer1 and mPer2, two mammalian clock genes, in murine bone marrow. Biochem Biophys Res Commun 2000;276:724–8. [48] Teboul M, Barrat-Petit M-A, Mei Li X, Claustrat B, Formento J-L, Delaunay F, et al. Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells. J Mol Med 2005;83: 693–9. [49] Bourin P, Ledain AF, Beau J, Mille D, Levi F. In-vitro circadian rhythm of murine bone marrow progenitor production. Chronobiol Int 2002;19:57– 67. [50] Wehr TA, Aeschbach D, Duncan WC. Evidence for a biological dawn and dusk in the human circadian timing system. J Physiol (London) 2001;535:937–51. [51] Hou ZH, Xin HW. Optimal system size for mesoscopic chemical oscillation. Chemphyschem 2004;5:407–10. [52] Yi M, Jia Y, Liu Q, Li JR, Zhu CL. Enhancement of internal-noise coherence resonance by modulation of external noise in a circadian oscillator. Phys Rev E 2006;73. art no 041923 part 1. [53] Fu LN. The circadian gene period2 plays an important role in tumor suppression and DANN-damage response in vivo. Cell 2002;111:41–50. [54] Filipski E, King VM, Etienne M-C, Li X, Claustrat B, Granda TG, et al. Persistent twenty-four hour changes in liver and bone marrow sepite suprachiasmatic nuclei ablation in mice. Am J Physiol Regulat Integr Comp Physiol 2004;287:R844–51.