Are Circadian Rhythms the Code of Hypothalamic-Immune Communication? Insights from Natural Killer Cells

Circadian rhythms in physiology and behavior are ultimately regulated at the hypothalamic level by the suprachiasmatic nuclei (SCN). This central oscillator transduces photic information to the cellular clocks in the periphery through the autonomic nervous system and the neuroendocrine system. The fact that these two systems have been shown to modulate leukocyte physiology supports the concept that the circadian component is an important aspect of hypothalamic-immune communication. Circadian disruption has been linked to immune dysregulation, and recent reports suggest that several circadian clock genes, in addition to their time-keeping role, are involved in the immune response. In this overview, we summarize the findings demonstrating that Natural Killer (NK) cell function is under circadian control.

[1]  P. Mellon,et al.  Circadian Gene Expression Regulates Pulsatile Gonadotropin-Releasing Hormone (GnRH) Secretory Patterns in the Hypothalamic GnRH-Secreting GT1-7 Cell Line , 2003, The Journal of Neuroscience.

[2]  O. Tsitsilonis,et al.  Compromised anti‐tumor responses in tumor necrosis factor‐α knockout mice , 2000, European journal of immunology.

[3]  D. Sarkar,et al.  Circadian Oscillations of Clock Genes, Cytolytic Factors, and Cytokines in Rat NK Cells1 , 2005, The Journal of Immunology.

[4]  Lieping Chen,et al.  Renewed interest in cancer immunotherapy with the tumor necrosis factor superfamily molecules , 2006, Cancer Immunology, Immunotherapy.

[5]  K. Kristensson,et al.  Suppressors, receptors and effects of cytokines on the aging mouse biological clock , 2007, Neurobiology of Aging.

[6]  R. Herberman,et al.  Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells , 1975, International journal of cancer.

[7]  C. Janeway,et al.  Innate immune recognition. , 2002, Annual review of immunology.

[8]  H. Kraemer,et al.  Diurnal cortisol rhythm as a predictor of breast cancer survival. , 2000, Journal of the National Cancer Institute.

[9]  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.

[10]  Xiaojing Ma,et al.  The Circadian Clock Period 2 Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock , 2006, Infection and Immunity.

[11]  Satchidananda Panda,et al.  The Transcriptional Repressor STRA13 Regulates a Subset of Peripheral Circadian Outputs* , 2004, Journal of Biological Chemistry.

[12]  L. Moretta,et al.  CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  D. Boivin,et al.  Circadian clock genes oscillate in human peripheral blood mononuclear cells. , 2003, Blood.

[14]  B. Robertson,et al.  Expression of an oscillating interferon‐γ receptor in the suprachiasmatic nuclei , 1998 .

[15]  G. Ferreyra,et al.  Circadian and photic regulation of ERK, JNK and p38 in the hamster SCN , 2003, Neuroreport.

[16]  G. Trinchieri,et al.  Biology of Natural Killer Cells , 1989, Advances in Immunology.

[17]  Paolo Sassone-Corsi,et al.  Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Shibata,et al.  Adrenergic regulation of clock gene expression in mouse liver , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Bleackley,et al.  Cytotoxic T lymphocytes: all roads lead to death , 2002, Nature Reviews Immunology.

[20]  P. Razeghi,et al.  Clock Genes in the Heart: Characterization and Attenuation With Hypertrophy , 2001, Circulation research.

[21]  R. Zinkernagel,et al.  Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors , 1995, Journal of virology.

[22]  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.

[23]  S. Shimba,et al.  Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Miller,et al.  Exogenous melatonin: quantitative enhancement in vivo of cells mediating non-specific immunity , 2000, Journal of Neuroimmunology.

[25]  Mark J. Smyth,et al.  Functional significance of the perforin/granzyme cell death pathway , 2002, Nature Reviews Immunology.

[26]  D. Sarkar,et al.  Short Communication: The Circadian Gene mPer2 Regulates the Daily Rhythm of IFN-γ , 2006 .

[27]  Keith Hoots,et al.  Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS , 2002, Nature Genetics.

[28]  P. Hardin.  Transcription Regulation within the Circadian Clock: The E-box and Beyond , 2004, Journal of biological rhythms.

[29]  Francine Laden,et al.  Night-shift work and risk of colorectal cancer in the nurses' health study. , 2003, Journal of the National Cancer Institute.

[30]  P. Reynolds,et al.  Cancer incidence in California flight attendants (United States) , 2002, Cancer Causes & Control.

[31]  T. Nagase,et al.  Humoral signals mediate the circadian expression of rat period homologue (rPer2) mRNA in peripheral tissues , 1998, Neuroscience Letters.

[32]  D. Sarkar,et al.  The circadian gene mPer2 regulates the daily rhythm of IFN-gamma. , 2006, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[33]  S. Felten,et al.  Chapter 20 Neural-immune interactions , 1994 .

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

[35]  Paolo Sassone-Corsi,et al.  Time after time: inputs to and outputs from the mammalian circadian oscillators , 2002, Trends in Neurosciences.

[36]  H. Romijn,et al.  Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway , 1999, The European journal of neuroscience.

[37]  E. Shimizu,et al.  Daily expression of mRNAs for the mammalian Clock genes Per2 and clock in mouse suprachiasmatic nuclei and liver and human peripheral blood mononuclear cells. , 2002, Japanese journal of pharmacology.

[38]  F. Lévi,et al.  Circadian‐system alterations during cancer processes: A review , 1997, International journal of cancer.

[39]  J. Clot,et al.  Interferon-alpha restores HIV-induced alteration of natural killer cell perforin expression in vivo. , 2003, AIDS.

[40]  J. Trapani,et al.  Initiation of Apoptosis by Granzyme B Requires Direct Cleavage of Bid, but Not Direct Granzyme B–Mediated Caspase Activation , 2000, The Journal of experimental medicine.

[41]  R. Straub.  Complexity of the bi-directional neuroimmune junction in the spleen. , 2004, Trends in pharmacological sciences.

[42]  B. H. Miller,et al.  Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock , 2002, Cell.

[43]  A. Yasui,et al.  Disruption of mCry 2 restores circadian rhythmicity in mPer 2 mutant mice , 2002 .

[44]  R. Sun,et al.  Recombinant Human Prolactin Improves Antitumor Effects of Murine Natural Killer Cells in vitro and in vivo , 2002, Neuroimmunomodulation.

[45]  C. Biron,et al.  NK cells and NKT cells in innate defense against viral infections. , 2001, Current opinion in immunology.

[46]  A. B. Reddy,et al.  A clockwork web: circadian timing in brain and periphery, in health and disease , 2003, Nature Reviews Neuroscience.

[47]  F. Halberg,et al.  Circadian rhythm in activity of lympholytic natural killer cells from spleens of Fischer rats. , 1979, Journal of immunology.

[48]  K. Mishima,et al.  Similar profiles in human period1 gene expression in peripheral mononuclear and polymorphonuclear cells , 2004, Neuroscience Letters.

[49]  K. Yau,et al.  Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity , 2002, Science.

[50]  D. Cardinali,et al.  Twenty-Four-Hour Rhythms in Immune Responses in Rat Submaxillary Lymph Nodes and Spleen: Effect of Cyclosporine , 1996, Brain, Behavior, and Immunity.

[51]  Z. Kronfol,et al.  Circadian Immune Measures in Healthy Volunteers: Relationship to Hypothalamic-Pituitary-Adrenal Axis Hormones and Sympathetic Neurotransmitters , 1997, Psychosomatic medicine.

[52]  Zhihui Yang,et al.  MOP3, a component of the molecular clock, regulates the development of B cells , 2006, Immunology.

[53]  C. Biron,et al.  Natural killer cells in antiviral defense: function and regulation by innate cytokines. , 1999, Annual review of immunology.

[54]  M. Smyth,et al.  Close encounters of different kinds: Dendritic cells and NK cells take centre stage , 2005, Nature Reviews Immunology.

[55]  M. Nagano,et al.  A partial hepatectomy results in altered expression of clock-related and cyclic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) genes. , 2004, Life sciences.

[56]  C. Gardiner,et al.  Putting the natural killer cell in its place , 2006, Immunology.

[57]  Lloyd J. Old,et al.  The roles of IFNγ in protection against tumor development and cancer immunoediting , 2002 .

[58]  J Lellouch,et al.  Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[59]  M. Smyth,et al.  Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. , 2001, Blood.

[60]  Peng Huang,et al.  The Circadian Gene Period2 Plays an Important Role in Tumor Suppression and DNA Damage Response In Vivo , 2002, Cell.

[61]  S. Felten,et al.  Neural-immune interactions. , 1994, Progress in brain research.

[62]  K. Kadota,et al.  Genome-wide Expression Analysis of Mouse Liver Reveals CLOCK-regulated Circadian Output Genes* , 2003, Journal of Biological Chemistry.

[63]  G. Shakhar,et al.  Diurnal changes in lung tumor clearance and their relation to NK cell cytotoxicity in the blood and spleen , 2001, International journal of cancer.

[64]  K. Kadota,et al.  Clock mutation affects circadian regulation of circulating blood cells , 2006, Journal of circadian rhythms.

[65]  Ueli Schibler,et al.  Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts , 2000, Current Biology.

[66]  D. Sarkar,et al.  Chronic Ethanol Inhibits NK Cell Cytolytic Activity: Role of Opioid Peptide β-Endorphin1 , 2001, The Journal of Immunology.

[67]  G. Lincoln,et al.  Clock Genes and the Long‐Term Regulation of Prolactin Secretion: Evidence for a Photoperiod/Circannual Timer in the Pars Tuberalis , 2003, Journal of neuroendocrinology.

[68]  S. Reppert,et al.  Coordination of circadian timing in mammals , 2002, Nature.

[69]  A. Auvinen,et al.  Incidence of cancer among Nordic airline pilots over five decades: occupational cohort study , 2002, BMJ : British Medical Journal.

[70]  T. Nagase,et al.  Antiphase circadian expression between BMAL1 and period homologue mRNA in the suprachiasmatic nucleus and peripheral tissues of rats. , 1998, Biochemical and biophysical research communications.

[71]  O. Tsitsilonis,et al.  Compromised anti-tumor responses in tumor necrosis factor-alpha knockout mice. , 2000, European journal of immunology.

[72]  S. Perez,et al.  Natural killer lymphocytes: biology, development, and function , 2004, Cancer Immunology, Immunotherapy.

[73]  G. Beatty,et al.  Regulation of tumor growth by IFN-gamma in cancer immunotherapy. , 2001, Immunologic research.

[74]  E. Podack,et al.  Perforin, Fas ligand, and tumor necrosis factor are the major cytotoxic molecules used by lymphokine-activated killer cells. , 1996, Journal of immunology.

[75]  Kai-Florian Storch,et al.  Extensive and divergent circadian gene expression in liver and heart , 2002, Nature.

[76]  F. Carandente,et al.  Circadian changes in human natural killer-cell activity. , 1987, Progress in clinical and biological research.

[77]  J. Clot,et al.  Interferon-α restores HIV-induced alteration of natural killer cell perforin expression in vivo , 2003 .

[78]  Franck Delaunay,et al.  Effects of Chronic Jet Lag on Tumor Progression in Mice , 2004, Cancer Research.

[79]  P. Kuppen,et al.  NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. , 2003, Trends in immunology.

[80]  F. Davis,et al.  Transplanted suprachiasmatic nucleus determines circadian period. , 1990, Science.

[81]  R. Biassoni,et al.  Human natural killer cells: their origin, receptors and function , 2002, European journal of immunology.

[82]  M. Snyder,et al.  The double life of NK receptors: stimulation or co-stimulation? , 2004, Trends in immunology.

[83]  F Laden,et al.  Rotating night shifts and risk of breast cancer in women participating in the nurses' health study. , 2001, Journal of the National Cancer Institute.

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

[85]  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.

[86]  H. Korf,et al.  Melatonin: A Clock‐Output, A Clock‐Input , 2003 .

[87]  U. Finckh,et al.  Indication of circadian oscillations in the rat pancreas , 2004, FEBS letters.

[88]  T. Katafuchi,et al.  Hypothalamic modulation of splenic natural killer cell activity in rats. , 1993, The Journal of physiology.

[89]  A. Angulo,et al.  NK cell receptors involved in the response to human cytomegalovirus infection. , 2006, Current topics in microbiology and immunology.

[90]  Johanna H. Meijer,et al.  In Search of the Pathways for Light-Induced Pacemaker Resetting in the Suprachiasmatic Nucleus , 2003, Journal of biological rhythms.

[91]  P. Tresco,et al.  A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms , 1996, Nature.

[92]  D. Raulet.  Interplay of natural killer cells and their receptors with the adaptive immune response , 2004, Nature Immunology.

[93]  Fred W. Turek,et al.  Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice , 2005, Science.

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

[95]  J. Kirkwood,et al.  Helper role of NK cells during the induction of anticancer responses by dendritic cells. , 2005, Molecular immunology.

[96]  J. Trapani,et al.  Cytotoxic cell granule-mediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. , 2002, Immunity.

[97]  R. Reiter,et al.  A review of the multiple actions of melatonin on the immune system , 2005, Endocrine.

[98]  Shishir Shishodia,et al.  The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. , 2002, Current drug targets. Inflammation and allergy.

[99]  Erik Maronde,et al.  The human PER1 gene is inducible by interleukin-6 , 2002, Journal of Molecular Neuroscience.

[100]  A. Angeli.  Circadian rhythms of human NK cell activity. , 1992, Chronobiologia.

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

[102]  B. Bonavida,et al.  Mechanism of Norepinephrine-Mediated Inhibition of Human NK Cytotoxic Functions: Inhibition of Cytokine Secretion, Target Binding, and Programming for Cytotoxicity , 2002, Brain, Behavior, and Immunity.

[103]  G. Korbutt,et al.  Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is a Death Receptor for Granzyme B during Cytotoxic T Cell–Induced Apoptosis , 2000, Cell.

[104]  Toshiyuki Okano,et al.  Glucose Down-regulates Per1 and Per2mRNA Levels and Induces Circadian Gene Expression in Cultured Rat-1 Fibroblasts* 210 , 2002, The Journal of Biological Chemistry.

[105]  J. Tschopp,et al.  A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[106]  Hans Hengartner,et al.  Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice , 1994, Nature.

[107]  D. Sarkar,et al.  Circadian Rhythms of Granzyme B, Perforin, IFN-γ, and NK Cell Cytolytic Activity in the Spleen: Effects of Chronic Ethanol1 , 2004, The Journal of Immunology.

[108]  K. Oishi,et al.  Differential expressions of mPer1 and mPer2 mRNAs under a skeleton photoperiod and a complete light-dark cycle. , 2002, Brain research. Molecular brain research.

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

[110]  S. Martinotti,et al.  Interleukin-2-activated rat natural killer cells express inducible nitric oxide synthase that contributes to cytotoxic function and interferon-gamma production. , 1999, Blood.

[111]  G. Eichele,et al.  The mPer2 gene encodes a functional component of the mammalian circadian clock , 1999, Nature.

[112]  M. Smyth,et al.  Innate Immune Surveillance of Spontaneous B Cell Lymphomas by Natural Killer Cells and γδ T Cells , 2004, The Journal of experimental medicine.

[113]  Borries Demeler,et al.  Cytotoxic Cell Granule-mediated Apoptosis , 2002, The Journal of Biological Chemistry.

[114]  Erik D Herzog,et al.  Clock Genes, Oscillators, and Cellular Networks in the Suprachiasmatic Nuclei , 2004, Journal of biological rhythms.

[115]  A. Kalsbeek,et al.  The biological clock tunes the organs of the body: timing by hormones and the autonomic nervous system. , 2003, The Journal of endocrinology.

[116]  F. Fleury-Olela,et al.  Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. , 2000, Genes & development.

[117]  L. Kaer,et al.  IFN-γ–mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, α-galactosylceramide , 2002 .

[118]  G. Beatty,et al.  Regulation of tumor growth by IFN-γ in cancer immunotherapy , 2001 .

[119]  J. Beckmann,et al.  Circadian regulation of islet genes involved in insulin production and secretion , 2004, Molecular and Cellular Endocrinology.

[120]  R. Handa,et al.  Circadian analysis of mononuclear cells in the rat following pinealectomy and superior cervical ganglionectomy , 1990, Brain, Behavior, and Immunity.

[121]  J. Schatzle,et al.  Functional Defects of NK Cells Treated with Chloroquine Mimic the Lytic Defects Observed in Perforin-Deficient Mice1 , 2000, The Journal of Immunology.

[122]  M. Caligiuri,et al.  What does it take to make a natural killer? , 2003, Nature Reviews Immunology.

[123]  P. J. Larsen,et al.  Distribution of neuropeptide Y receptor expression in the rat suprachiasmatic nucleus. , 1998, Brain research. Molecular brain research.

[124]  Jie Zhou,et al.  Glucocorticoid regulation of natural cytotoxicity: effects of cortisol on the phenotype and function of a cloned human natural killer cell line. , 1997, Cellular immunology.

[125]  Hiroaki Ikeda,et al.  The roles of IFN gamma in protection against tumor development and cancer immunoediting. , 2002, Cytokine & growth factor reviews.

[126]  Ook Joon Yoo,et al.  PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[127]  J. Born,et al.  A regulatory role of prolactin, growth hormone, and corticosteroids for human T-cell production of cytokines , 2004, Brain, Behavior, and Immunity.

[128]  J. Trapani,et al.  Granzyme B (GraB) Autonomously Crosses the Cell Membrane and Perforin Initiates Apoptosis and GraB Nuclear Localization , 1997, The Journal of experimental medicine.

[129]  A. Yasui,et al.  Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice. , 2002, Genes & development.

[130]  Satchidananda Panda,et al.  BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in Glucose Homeostasis , 2004, PLoS biology.

[131]  H. Romijn,et al.  Parasympathetic and sympathetic control of the pancreas: A role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake , 2001, The Journal of comparative neurology.

[132]  Francis Lévi,et al.  Disruption of circadian coordination accelerates malignant growth in mice. , 2003, Pathologie-biologie.