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Links between the innate immune system and sleep

2005; Elsevier BV; Volume: 116; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2005.08.005

1097-6825

Jeannine A. Majde, James M. Krueger,

Sleep and Wakefulness Research

Sleep is a fundamental physiologic process with unknown functions. It is divided into 2 distinct states: non–rapid-eye-movement sleep and rapid-eye-movement sleep. After acute infection with nonneurotropic agents, there are stereotypic changes in non–rapid-eye-movement sleep, particularly increased time spent in slow-wave sleep, and often a reduction of time spent in rapid-eye-movement sleep. It is now recognized that both infection-associated sleep and spontaneous sleep are regulated, in part, by immune mediators called cytokines. This review provides brief tutorials on the elements of the innate immune system that detect infection, how sleep is characterized in the laboratory, issues regarding the interpretation of sleep effects on immune function, the interaction of sleep with circadian rhythms and stress, and some of the microbial products, cytokines, and neuropeptides associated with sleep regulation. We also summarize our current understanding of the role of sleep in host defense and asthma exacerbation. Sleep is a fundamental physiologic process with unknown functions. It is divided into 2 distinct states: non–rapid-eye-movement sleep and rapid-eye-movement sleep. After acute infection with nonneurotropic agents, there are stereotypic changes in non–rapid-eye-movement sleep, particularly increased time spent in slow-wave sleep, and often a reduction of time spent in rapid-eye-movement sleep. It is now recognized that both infection-associated sleep and spontaneous sleep are regulated, in part, by immune mediators called cytokines. This review provides brief tutorials on the elements of the innate immune system that detect infection, how sleep is characterized in the laboratory, issues regarding the interpretation of sleep effects on immune function, the interaction of sleep with circadian rhythms and stress, and some of the microbial products, cytokines, and neuropeptides associated with sleep regulation. We also summarize our current understanding of the role of sleep in host defense and asthma exacerbation. The innate immune system of mammals comprises numerous antimicrobial mechanisms,1Basset C. Holton J. O'Mahony R. Roitt I. Innate immunity and pathogen-host interaction.Vaccine. 2003; 21: S12-S23Crossref PubMed Scopus (54) Google Scholar some of which can be traced back to the first multicellular organisms. Until recently, study of the innate immune system has taken a back seat to the more evolutionarily advanced acquired immune system. In the last decade, however, the emphasis in immunology has shifted to innate immune mechanisms with the discovery of certain key concepts and molecular classes described below.2Germain R.N. An innately interesting decade of research in immunology.Nat Med. 2004; 10: 1307-1320Crossref PubMed Scopus (74) Google Scholar The innate immune system appears to have 2 primary functions: rapid isolation and destruction of invading pathogens (or foreign cells, such as tumors or transplants) through inflammatory processes and antigen recognition and processing for the acquired immune system. The acquired immune system, in turn, uses antibodies and cytotoxic cellular mechanisms that help clear residual microorganisms and, through immunologic memory, speed up their detection and removal in future reinfections. In the context of infection, both of these innate immune functions require distinguishing pathogenic microorganisms from the self. In recent years, microbiologists have characterized an evolutionarily conserved receptor system that appears to be the major cell membrane–bound system for pathogen recognition. This receptor system has been named the Toll-like receptor (TLR) system after the Toll system of fruit flies,3Kaisho T. Akira S. Pleiotropic function of Toll-like receptors.Microbes Infect. 2004; 6: 1388-1394Crossref PubMed Scopus (87) Google Scholar where this class of pathogen-associated molecular pattern (PAMP) recognition receptors was first identified. Currently, TLRs comprise 13 receptors (some found in mice, some found in human subjects, and most shared by both species4Bowie A.G. Haga I.R. The role of Toll-like receptors in the host response to viruses.Mol Immunol. 2005; 42: 859-867Crossref PubMed Scopus (143) Google Scholar) that recognize a range of PAMPs unique to microorganisms. These PAMPs include the LPS on the surface of gram-negative bacteria (TLR4), lipopeptides on gram-positive bacteria and mycoplasma (TLR2, TLR1, and TLR6),5Travassos L.H. Girardin S.E. Philpott D.J. Blanot D. Nahori M.A. Werts C. et al.Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition.EMBO Rep. 2004; 5: 1000-1006Crossref PubMed Scopus (294) Google Scholar, 6Kawai T. Akira S. Pathogen recognition with Toll-like receptors.Curr Opin Immunol. 2005; 17: 338-344Crossref PubMed Scopus (290) Google Scholar fungal polysaccharides (TLR2), bacterial flagellae (TLR5 and TLR11),6Kawai T. Akira S. Pathogen recognition with Toll-like receptors.Curr Opin Immunol. 2005; 17: 338-344Crossref PubMed Scopus (290) Google Scholar unmethylated bacterial and viral DNA (TLR9), guanosine-uridine–rich viral RNA (TLR7 and TLR8),7Heil F. Hemmi H. Hochrein H. Ampenberger F. Kirschning C. Akira S. et al.Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8.Science. 2004; 303: 1526-1529Crossref PubMed Scopus (1738) Google Scholar or the double-stranded RNA (dsRNA) induced during viral replication (TLR3).3Kaisho T. Akira S. Pleiotropic function of Toll-like receptors.Microbes Infect. 2004; 6: 1388-1394Crossref PubMed Scopus (87) Google Scholar TLRs all possess amino-terminal leucine-rich repeats that are responsible for PAMP recognition, as well as a carboxy-terminal TLR1 receptor domain required for intracellular signaling.6Kawai T. Akira S. Pathogen recognition with Toll-like receptors.Curr Opin Immunol. 2005; 17: 338-344Crossref PubMed Scopus (290) Google Scholar Most TLRs are expressed on the cell surface, but those that recognize nucleic acids are all expressed in endosomal compartments.6Kawai T. Akira S. Pathogen recognition with Toll-like receptors.Curr Opin Immunol. 2005; 17: 338-344Crossref PubMed Scopus (290) Google Scholar Soluble factors are also involved in pathogen recognition and can work in association with TLRs and with more generic scavenger, complement, and lectin receptors on phagocytes.1Basset C. Holton J. O'Mahony R. Roitt I. Innate immunity and pathogen-host interaction.Vaccine. 2003; 21: S12-S23Crossref PubMed Scopus (54) Google Scholar Selected bacterial PAMPs, the peptidoglycans, are also sensed by a family of cytoplasmic proteins, termed the nucleotide-binding site/leucine-rich repeat proteins.8Girardin S.E. Travassos L.H. Herve M. Blanot D. Boneca I.G. Philpott D.J. et al.Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2.J Biol Chem. 2003; 278: 41702-41708Crossref PubMed Scopus (325) Google Scholar This family of pathogen recognition receptors has recently been dubbed NLRs (NACHT–leucine-rich repeat bearing proteins) for convenience.9Martinon F. Tschopp J. NLRs join TLRs as innate sensors of pathogens.Trends Immunol. 2005; 26: 447-454Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar The best studied members of this cytoplasmic system are the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2.6Kawai T. Akira S. Pathogen recognition with Toll-like receptors.Curr Opin Immunol. 2005; 17: 338-344Crossref PubMed Scopus (290) Google Scholar Peptidoglycans are a major structural component of all bacterial cell walls, and NODs can distinguish gram-negative and gram-positive peptidoglycans.10Viala J. Sansonetti P. Philpott D.J. Nods and ‘intracellular’ innate immunity.Compt Rend Biol. 2004; 327: 551-555Crossref PubMed Scopus (28) Google Scholar There is controversy as to whether peptidoglycans are recognized by TLR2 on the cell surface, as well as intracellular NLRs.11Dziarski R. Gupta D. Staphylococcus aureus peptidoglycan is a Toll-like receptor 2 activator: a reevaluation.Infect Immun. 2005; 73: 5212-5216Crossref PubMed Scopus (142) Google Scholar Elucidation of the PAMPS for TLRs and related proteins have provided valuable insights into the cause of such human diseases as Crohn's bowel disease and recurrent bladder infections.6Kawai T. Akira S. Pathogen recognition with Toll-like receptors.Curr Opin Immunol. 2005; 17: 338-344Crossref PubMed Scopus (290) Google Scholar Major effector cells in the innate immune system are the circulating phagocytic leukocytes (neutrophils and monocytes), natural killer cells (NK cells), natural killer T lymphocytes (NK T cells), and γδ T lymphocytes. Fixed macrophages and dendritic cells are widely distributed throughout tissues. All of these cells express TLRs that recognize pathogens. TLRs have only recently been found on NK cells12Sivori S. Falco M. Chiesa M.D. Carlomagno S. Vitale M. Moretta L. 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.Proc Natl Acad Sci U S A. 2004; 101: 10116-10121Crossref PubMed Scopus (263) Google Scholar and γδ T cells.13Hedges J.F. Lubick K.J. Jutila M.A. γδ T cells respond directly to pathogen-associated molecular patterns.J Immunol. 2005; 174: 6045-6053PubMed Google Scholar A central function of phagocytes is to recognize, engulf, and (ideally) destroy pathogens through several mechanisms, often involving oxygen and nitrogen free radicals. NK cells and cytotoxic NK T cells also play a key role in eliminating infected or otherwise altered cells, such as tumor cells.2Germain R.N. An innately interesting decade of research in immunology.Nat Med. 2004; 10: 1307-1320Crossref PubMed Scopus (74) Google Scholar, 14Belardelli F. Ferrantini M. Cytokines as a link between innate and adaptive antitumor immunity.Trends Immunol. 2002; 23: 201-208Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar Dendritic cells are key antigen-processing cells and form a central link between innate and acquired immunity.2Germain R.N. An innately interesting decade of research in immunology.Nat Med. 2004; 10: 1307-1320Crossref PubMed Scopus (74) Google Scholar Tissue mast cells (which also express TLRs15Kulka M. Alexopoulou L. Flavell R.A. Metcalfe D.D. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3.J Allergy Clin Immunol. 2004; 114: 174-182Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar) and enterochromaffin cells16Cooke H.J. Neurotransmitters in neuronal reflexes regulating intestinal secretion.Ann N Y Acad Sci. 2000; 915: 77-80Crossref PubMed Google Scholar also play a role in innate immunity through release of vasoactive factors, such as histamine and serotonin. All of these cells release cytokines when invaded by microbes or when stimulated by other cytokines or mediators released in the course of inflammation. Cytokines are an enormously complex network of peptide-signaling molecules that are synthesized by immune cells activated by PAMP recognition.17Krueger J.M. Majde J.A. Host defense.in: Kryger M.H. Roth T. Dement W.C. Principles and practice of sleep medicine. Elsevier Saunders, Philadelphia2005: 256-265Crossref Scopus (7) Google Scholar Cytokines are also made by infected epithelial cells, endothelial cells, and virtually any other cell when appropriately stimulated, although the specific types made18Agace W. Hedges S. Andersson U. Andersson J. Ceska M. Svanborg C. Selective cytokine production by epithelial cells following exposure to Escherichia coli.Infect Immun. 1993; 61: 602-609PubMed Google Scholar and quantities produced per cell might differ from phagocytes. More than 100 cytokines have been identified, several of which are key regulators of allergy and asthma responses.19Gelfand E.W. Inflammatory mediators in allergic rhinitis.J Allergy Clin Immunol. 2004; 114: S135-S138Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar The cytokines are generally classified as proinflammatory (type I) or anti-inflammatory (type II) and include classical endocrine hormones, such as prolactin and growth hormone, as well as chemotactic chemokines and immunomodulatory type I IFNs as subsets.14Belardelli F. Ferrantini M. Cytokines as a link between innate and adaptive antitumor immunity.Trends Immunol. 2002; 23: 201-208Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar The release of cytokines from infected cells alerts neighboring cells through paracrine mechanisms that the host is under attack. This cytokine signaling induces protective cytokines (eg, IFNs) in those neighboring cells and stimulates chemotaxis of inflammatory cells, such as neutrophils, to supplement local defenses. In sufficient concentrations cytokines spill into the lymph and blood to act on the brain, liver, and bone marrow. Circulating cytokines act on brain capillary endothelium to induce pyrogenic prostaglandins and enter the brain parenchyma through specific transporters and at sites lacking a blood-brain barrier, such as the organum vasculosum of lamina terminalis and the median eminence of the hypothalamus.20Konsman J.P. Parnet P. Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications.Trends Neurosci. 2002; 25: 154-159Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar Once in the brain, proinflammatory cytokines induce themselves, as well as prostaglandins and anti-inflammatory cytokines.21Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity.Eur J Pharmacol. 2004; 500: 399-411Crossref PubMed Scopus (276) Google Scholar Extensive evidence indicates that cytokines also signal the brain through the vagus nerve (although this has recently been questioned22Romanovsky A. Almeida M.C. Aronoff D.M. Ivanov A.I. Konsman J.P. Steiner A.A. et al.Fever and hypothermia in systemic inflammation: recent discoveries and revisions.Front Biosci. 2005; 10: 2193-2216Crossref PubMed Google Scholar) and can thereby induce cytokine synthesis in selected regions of the brain.20Konsman J.P. Parnet P. Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications.Trends Neurosci. 2002; 25: 154-159Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar The accumulated systemic and brain proinflammatory cytokines initiate a complex and protective physiologic response termed the acute-phase response (APR).23Krueger J.M. Majde J.A. Humoral links between sleep and the immune system. Research issues.Ann N Y Acad Sci. 2003; 992: 9-20Crossref PubMed Google Scholar The most commonly studied physiologic APR is fever. Our laboratory has characterized one of the even more complex APRs, excess slow-wave sleep (SWS). Several recent reviews17Krueger J.M. Majde J.A. Host defense.in: Kryger M.H. Roth T. Dement W.C. Principles and practice of sleep medicine. Elsevier Saunders, Philadelphia2005: 256-265Crossref Scopus (7) Google Scholar, 24Krueger J.M. Obal Jr., F. Fang J. Kubota T. Taishi P. The role of cytokines in physiological sleep regulation.Ann N Y Acad Sci. 2001; 933: 211-221Crossref PubMed Google Scholar, 25Krueger J.M. Majde J.A. Obal Jr., F. Sleep in host defense.Brain Behav Immun. 2003; 17: S41-S47Crossref PubMed Google Scholar, 26Majde J.A. Krueger J.M. Neuroimmunology of sleep.in: D'haenen H. Textbook of biological psychiatry. John Wiley & Sons, Ltd, London2002: 1247-1257Google Scholar, 27Obal Jr., F. Krueger J.M. Biochemical regulation of non-rapid-eye-movement sleep.Front Biosci. 2003; 8: 520-550Crossref PubMed Google Scholar, 28Bryant P.A. Trinder J. Curtis N. Sick and tired: does sleep have a vital role in the immune system.Nat Rev Immunol. 2004; 4: 457-467Crossref PubMed Google Scholar, 29Benca R.M. Quintas J. Sleep and host defenses: a review.Sleep. 1997; 20: 1027-1037PubMed Google Scholar, 30Opp M.R. Cytokines and sleep: the first hundred years.Brain Behav Immun. 2004; 18: 295-297Crossref PubMed Scopus (6) Google Scholar, 31Dickstein J.B. Moldofsky H. 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All mammals sleep, although in radically different amounts and patterns. For example, aquatic mammals sleep on one side of the brain at a time to avoid drowning.33Zepelin H. Siegel J.M. Tobler I. Mammalian sleep.in: Kryger M.H. Roth T. Dement W.C. Principles and practice of sleep medicine. Elsevier Saunders, Philadelphia2005: 91-100Crossref Scopus (59) Google Scholar In an effort to better understand physiologic sleep, our studies have focused on sleep alterations that occur after challenge with microbial products of the type detected by TLRs and NODs or after actual infection. Whether physiologic or pathologic, sleep is divided into 2 states: non–rapid-eye-movement sleep (NREMS; quiet sleep) and rapid-eye-movement sleep (REMS; paradoxical sleep or dream sleep). These 2 states manifest very differently and appear to be regulated by different regions of the brain.34Espana R.A. Scammell T.E. Sleep neurobiology for the clinician.Sleep. 2005; 27: 811-820Google Scholar NREMS and REMS are defined by electroencephalographic (EEG) brain wave patterns, the amount of eye movement, and brain temperature by using EEG electrodes, electromyographic electrodes, and thermistors applied in or near the brain, respectively.35Krueger J.M. Kapas L. Kimura M. Opp M.R. Somnogenic cytokines: methods and overview.in: DeSouza E.D. Neurobiology of cytokines. [17, Part B]. Academic Press, Orlando (FL)1993: 111-129Crossref Google Scholar The process of collecting and integrating all of these various data to quantify sleep states is termed polysomnography. NREMS is divided into 4 stages in human subjects, the latter 2 of which are characterized by high-amplitude EEG slow-wave activity (also called delta waves: frequencies between 0.5 and 4 Hz). In human subjects sleep is usually consolidated into an 8-hour period during the night. In contrast, most mammals are polyphasic sleepers. For instance, a rat SWS episode seldom lasts more than a few minutes, and sleep episodes occur throughout the day and night, although as a nocturnal species, they do sleep more during the day. We have observed in animals that the total amount of SWS is increased during infection or after challenge with microbial products or certain cytokines.25Krueger J.M. Majde J.A. Obal Jr., F. Sleep in host defense.Brain Behav Immun. 2003; 17: S41-S47Crossref PubMed Google Scholar Another characteristic of infection-associated SWS is increased amplitudes of the EEG delta waves, which are thought to be a measure of sleep intensity.36Opp M.R. Toth L.A. Tolley E.A. EEG delta power and auditory arousal in rested and sleep-deprived rabbits.Am J Physiol Regul Integr Compar Physiol. 1997; 272: R648-R655Google Scholar Time spent in NREMS and slow-wave amplitudes are the 2 measures that best characterize sleep changes after infection. REMS comprises about 25% of the sleep time in human subjects but less than 10% of the sleep time in rodents.33Zepelin H. Siegel J.M. Tobler I. Mammalian sleep.in: Kryger M.H. Roth T. Dement W.C. Principles and practice of sleep medicine. Elsevier Saunders, Philadelphia2005: 91-100Crossref Scopus (59) Google Scholar Time in REMS is reduced in more severe inflammatory states. One of the intrinsic regulators of REMS appears to be endogenous type I IFNs because spontaneous REMS is substantially suppressed in the absence of the type I IFN receptor.37Bohnet S.G. Traynor T.R. Majde J.A. Kacsoh B. Krueger J.M. Mice deficient in the interferon type I receptor have reduced REM sleep and altered hypothalamic hypocretin, prolactin and 2′,5′-oligoadenylate synthase expression.Brain Res. 2004; 1027: 117-125Crossref PubMed Scopus (21) Google Scholar Frequently, excess SWS and fever (or hypothermia in small animals) coincide in infections, and because both are induced by the same stimuli, they are often assumed to be linked. Both SWS and body temperature are regulated by the hypothalamus, although by different regions. There are many circumstances in which these 2 APRs can be distinguished, and they appear to be independently regulated.38Krueger J.M. Majde J.A. Microbial products and cytokines in sleep and fever regulation.Crit Rev Immunol. 1994; 14: 355-379Crossref PubMed Google Scholar In fact, brain temperature characteristically decreases along with decreasing brain metabolic rate in normal NREMS, which is thought by some to reflect a restorative or restful function of NREMS.39Heller H.C. Temperature, thermoregulation, and sleep.in: Kryger M.H. Roth T. Dement W.C. Principles and practice of sleep medicine. Elsevier Saunders, Philadelphia2005: 292-304Crossref Scopus (28) Google Scholar Sleep regulation is intimately associated with circadian rhythm regulation. Obvious evidence of the association is that diurnal species sleep at night, whereas nocturnal species sleep primarily during the day.40Lavie P. Sleep-wake as a biological rhythm.Annu Rev Psychol. 2001; 52: 277-303Crossref PubMed Scopus (71) Google Scholar Although sleep rhythms can be disrupted by eliminating external cues, such as light-dark cycles, when those cues are available, sleep rhythms are clearly controlled by a circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus, as are temperature rhythms and numerous other biologic rhythms.40Lavie P. Sleep-wake as a biological rhythm.Annu Rev Psychol. 2001; 52: 277-303Crossref PubMed Scopus (71) Google Scholar Several genes expressed both in the suprachiasmatic nucleus and in nonneural tissues are involved in circadian rhythm regulation,41Lowrey P.L. Takahashi J.S. Mammalian circadian biology: elucidating genome-wide levels of temporal organization.Ann Rev Genomics Hum Gen. 2004; 5: 407-441Crossref PubMed Scopus (448) Google Scholar and the use of gene microarrays reveals that expression of several hundred genes in the mouse liver vary in a cyclical pattern over the course of a 24-hour day.41Lowrey P.L. Takahashi J.S. Mammalian circadian biology: elucidating genome-wide levels of temporal organization.Ann Rev Genomics Hum Gen. 2004; 5: 407-441Crossref PubMed Scopus (448) Google Scholar Currently, it is believed that the timing of sleep and wakefulness is mediated by 2 interconnected processes: a homeostatic regulatory process that increases during waking and decreases during sleep, together with a circadian clock-dependent mechanism.41Lowrey P.L. Takahashi J.S. Mammalian circadian biology: elucidating genome-wide levels of temporal organization.Ann Rev Genomics Hum Gen. 2004; 5: 407-441Crossref PubMed Scopus (448) Google Scholar Clock-dependent mechanisms clearly influence sleep-wake cycles during jet lag and appear responsible for chronic sleep disorders associated with inappropriate sleep-wake cycles, such as those that occur in shift workers.41Lowrey P.L. Takahashi J.S. Mammalian circadian biology: elucidating genome-wide levels of temporal organization.Ann Rev Genomics Hum Gen. 2004; 5: 407-441Crossref PubMed Scopus (448) Google Scholar The genes involved in circadian regulation of sleep are being vigorously investigated. Genes that appear important for sleep are the period genes and the cryptochrome genes that regulate them.42Wisor J.P. Kilduff T.S. Molecular genetic advances in sleep research and their relevance to sleep medicine.Sleep. 2005; 28: 357-367PubMed Google Scholar The importance of sleep for various host functions is generally studied by examining the effects of either acute or chronic sleep deprivation on the function of interest. Regrettably, sleep deprivation paradigms are not standardized, and it is difficult to compare results from different laboratories. More importantly, it is not possible to isolate sleep as an independent variable because during sleep, almost every physiologic variable changes relative to wakefulness. Furthermore, sleep regulation is intimately associated with the hypothalamic-pituitary axis,43Vgontzas A.N. Chrousos G.P. Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders.Endocrinol Metab Clin North Am. 2002; 31: 15-36Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar as indicated by the inhibition of spontaneous sleep with antagonists of corticotrophin-releasing hormone, such as astressin.44Chang F.C. Opp M.R. Role of corticotropin-releasing hormone in stressor-induced alterations of sleep in rat.Am J Physiol Regul Integr Compar Physiol. 2002; 283: R400-R407PubMed Google Scholar Although prolonged sleep loss is not associated with classical stress markers,29Benca R.M. Quintas J. Sleep and host defenses: a review.Sleep. 1997; 20: 1027-1037PubMed Google Scholar, 45Meerlo P. Koehl M. Van der Borght K. Turek F.W. Sleep restriction alters the hypothalamic-pituitary-adrenal response to stress.J Neuroendocrinol. 2002; 14: 397-402Crossref PubMed Scopus (91) Google Scholar perhaps because of hypothalamic failure,46Everson C.A. Nowak Jr., T.S. Hypothalamic thyrotropin-releasing hormone mRNA responses to hypothyroxinemia induced by sleep deprivation.Am J Physiol Endocrinol Metab. 2002; 283: E85-E93PubMed Google Scholar acute sleep loss is a potent stimulus of stress hormones in animals.45Meerlo P. Koehl M. Van der Borght K. Turek F.W. Sleep restriction alters the hypothalamic-pituitary-adrenal response to stress.J Neuroendocrinol. 2002; 14: 397-402Crossref PubMed Scopus (91) Google Scholar, 47Andersen M.L. Bignotto M. Machado R.B. Tufik S. Different stress modalities result in distinct steroid hormone responses by male rats.Braz J Med Biol Res. 2004; 37: 791-797Crossref PubMed Google Scholar, 48Samel A. Vejvoda M. Maass H. Sleep deficit and stress hormones in helicopter pilots on 7-day duty for emergency medical services.Aviat Space Environ Med. 2004; 75: 935-940PubMed Google Scholar The stress component might reflect the method used for overcoming the sleep urge because human volunteers do not demonstrate the increases in glucocorticoids seen in laboratory animals,49Dinges D.F. Douglas S.D. Hamarman S. Zaugg L. Kapoor S. Sleep deprivation and human immune function.Adv Neuroimmunol. 1995; 5: 97-110Abstract Full Text PDF PubMed Scopus (110) Google Scholar perhaps because they make a conscious decision to participate. (Alternatively, the sleep deprivation methods used in animals might be inherently more stressful than those used in human volunteers.) Experimental studies comparing REMS deprivation in rats with other classical laboratory stressors such as foot shock and restraint reveal that stress hormone responses, such as increased corticosterone and decreased testosterone levels, are greatest after acute REMS deprivation and are similar in rats to those seen after foot shock, a potent stressor.47Andersen M.L. Bignotto M. Machado R.B. Tufik S. Different stress modalities result in distinct steroid hormone responses by male rats.Braz J Med Biol Res. 2004; 37: 791-797Crossref PubMed Google Scholar Subacute sleep deprivation induces stress ulcers in rats.50Guo J.S. Chau J.F.L. Cho C.H. Koo M.W.L. Partial sleep deprivation compromises gastric mucosal integrity in rats.Life Sci. 2005; 77: 220-229Crossref PubMed Scopus (16) Google Scholar Restraint stress, well known to be immunosuppressive,51Sheridan J.F. Dobbs C. Brown D. Zwilling B. Psychoneuroimmunology: stress effects on pathogenesis and immunity during infection.Clin Microbiol Rev. 1994; 7: 200-212PubMed Google Scholar is a much milder inducer of stress hormones than is REMS deprivation,47Andersen M.L. Bignotto M. Machado R.B. Tufik S. Different stress modalities result in distinct steroid hormone responses by male rats.Braz J Med Biol Res. 2004; 37: 791-797Crossref PubMed Google Scholar but it can lead to an increase in REMS in rats.52Dewasmes G. Loos N. Delanaud S. Dewasmes D. Ramadan W. Pattern of rapid-eye movement sleep episode occurrence after an immobilization stress in the rat.Neurosci Lett. 2004; 355: 17-20Crossref PubMed Scopus (11) Google Scholar Regardless, acute stress is a powerful modulator of immune function,51Sheridan J.F. Dobbs C. Brown D. Zwilling B. Psychoneuroimmunology: stress effects on pathogenesis and immunity during infection.Clin Microbiol Rev. 1994; 7: 200-212PubMed Google Scholar and the effects of sleep deprivation on immunity in animals must be interpreted with care. Furthermore, most studies of immune competence in human volunteers use stimulated blood leukocyte responses. Such ex vivo studies can be confounded by the catecholamine increases associated with sleep deprivation,53Irwin M. Thompson J. Miller C. Gillin J.C. Ziegler M. Effects of sleep and sleep deprivation on catecholamine and interleukin-2 levels in humans: clinical implications.J Clin Endocrinol Metab. 1999; 84: 1979-1985Crossref PubMed Google Scholar which in turn might result in alterations in white blood cell