Cytokines and Sleep Mechanisms

  • James M. Krueger
  • Linda Toth
Part of the Hans Selye Symposia on Neuroendocrinology and Stress book series (HSSN, volume 3)


The primary thesis of this essay is that infectious disease induces changes in sleep and that these sleep alterations are mediated by cytokines. More specifically, we propose that specific microbial products stimulate cytokine production and that these cytokines, in turn, induce the changes in sleep that occur during infections. Included in this scheme is the proposal that the cytokine interleukin-1 (IL1) is also involved in physiological sleep regulation.


Sleep Deprivation Growth Hormone Release Sleep Regulation Sleep Rebound Muramyl Peptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    L.A. Toth and J.M. Krueger, Alteration of sleep in rabbits by Staphylococcus aureus infection, Infect. Immun. 56:1785 (1988).PubMedGoogle Scholar
  2. 2.
    J.R. Pappenheimer, G. Koski, V. Fencl, M.L. Karnovsky, and J.M. Krueger, Extraction of sleep-promoting factor S from cerebrospinal fluid and from brains of sleep-deprived animals, J. Neurophysiol. 38:1299 (1975).PubMedGoogle Scholar
  3. 3.
    L.A. Toth and J.M. Krueger, Effects of microbial challenge on sleep in rabbits, FASEB J. 3:2062 (1989).PubMedGoogle Scholar
  4. 4.
    L.A. Toth and J.M. Krueger, Somnogenic, pyrogenic and hematologic effects of experimental pasteurellosis in rabbits, Am. J. Physiol. 258:R536 (1990).Google Scholar
  5. 5.
    S. Kent, M. Price, and B. Satinoff, Fevers alters characteristics of sleep in rats, Physiol. Behav. 44:709 (1988).PubMedCrossRefGoogle Scholar
  6. 6.
    M. Kimura-Takeuchi, JA. Majde, L.A. Toth, and J.M. Krueger, Tolerance to virally-induced changes in sleep of rabbits, Sleep Res. 20:268 (1991).Google Scholar
  7. 7.
    L.A. Toth and J.M. Krueger, Sleep as a prognostic indicator during infectious disease in rabbits, Proc. Soc. Expt. Biol, and Med. 203:179 (1993).Google Scholar
  8. 8.
    R. Brown, G. Pang, A.J. Husband, and M.G. King, Suppression of immunity to influenza virus infection in the respiratory tract following sleep disturbance, Regional Immunol. 2:321 (1989).Google Scholar
  9. 9.
    C.A. Everson, Sustained sleep deprivation impairs host defense, Am. J. Physiol. (in press).Google Scholar
  10. 10.
    L. Johannsen, L.A. Toth, R.S. Rosenthal, M.R. Opp, F. Ob́al Jr., A.B. Cady, and J.M. Krueger, Somnogenic, pyrogenic and hematologic effects of bacterial peptidoglycan, Am. J. Physiol. 259:R182 (1990).Google Scholar
  11. 11.
    L. Johannsen, H. Labischinski, and J.M. Krueger, Somnogenic activity of pseudomurein in rabbits, Infection and Immunity 59:2502 (1991).PubMedGoogle Scholar
  12. 12.
    J.M. Krueger, Somnogenic activity of immune response modifiers, TIPS 11:122 (1990).PubMedGoogle Scholar
  13. 13.
    J.M. Krueger, J.R. Pappenheimer, and M.L. Karnovsky, Sleep-promoting effects of muramyl peptides, Proc. Nat. Acad. Sci. USA 79:6102 (1982).PubMedCrossRefGoogle Scholar
  14. 14.
    J.M. Krueger, J. Walter, M.L. Karnovsky, L. Chedid, J.P. Choay, P. Lefrancier, and E. Lederer, Muramyl peptides: variation of somnogenic activity with structure, J. Exp. Med. 159:68 (1984).PubMedCrossRefGoogle Scholar
  15. 15.
    J.M. Krueger, S. Kubillus, S. Shoham, and D. Davenne, Enhancement of slow-wave sleep by endotoxin and lipid A, Am. J. Physiol. 251:R591 (1986).Google Scholar
  16. 16.
    A.B. Cady, G. Riveau, L. Chedid, C.A. Dinarello, L. Johannsen, and J.M. Krueger, Interleukin-1-induced sleep and febrile responses differentially altered by a muramyl dipeptide derivative, Int. J. Immunopharma. 11:887 (1989).CrossRefGoogle Scholar
  17. 17.
    M.W. Vermeulen and G.R. Grey, Processing of Bacillus subtilis peptidoglycan by a mouse macrophase cell line, Infect. Immunity 46:476 (1984).Google Scholar
  18. 18.
    L. Johannsen, J. Wecke, F. Ob́al Jr., and J.M. Krueger, Macrophages produce somnogenic and pyrogenic muramyl peptides during the digestion of staphylococci, Am. J. Physiol. 260:R126 (1991).Google Scholar
  19. 19.
    JA. Majde, R.K. Brown, M.W. Jones, C.A. Dieffenbach, N. Maitra, J.M. Krueger, A.B. Cady, C.W. Smitka, and H.F. Maassab, Detection of toxic viral-associated double-stranded RNA (dsRNA) in influenza-infected lung, Microb. Pathogen. 10:105 (1991).CrossRefGoogle Scholar
  20. 20.
    J.M. Krueger, JA. Majde, C.M. Blatteis, J. Endsley, R.A. Ahokas, and A.B. Cady, Polyriboinosinic: polyriboytidlylic acid (poly I:C) enhances rabbit slow-wave sleep, Am. J. Physiol. 255:R748 (1988).Google Scholar
  21. 21.
    J.M. Krueger, F. Ob́al Jr., M. Opp, L. Toth, L. Johannsen, and A.B. Cady, Somnogenic cytokines and models concerning their effects on sleep, Yale J. Biol. Med. 63:157 (1990).PubMedGoogle Scholar
  22. 22.
    M. Opp, F. Ob́al Jr., and J.M. Krueger, Responsiveness of rats to interleukin-1: Temporal dose-related effects, Am. J. Physiol. 260:R52 (1991).Google Scholar
  23. 23.
    I. Tobler, AA. Borb́ely, M. Schwyzer, and A. Fontana, Interleukin-1 derived from astrocytes enhances slow-wave activity in sleep EEG of the rat, Eur. J. Pharmacol. 104:191 (1984).PubMedCrossRefGoogle Scholar
  24. 24.
    V. Susic and S. Totic, “Recovery” function of sleep: effects of purified human interleukin-1 on the sleep and febrile response of cats, Met. Brain Dis. 4:73 (1989).CrossRefGoogle Scholar
  25. 25.
    J.M. Krueger, J. Walter, C.A. Dinarello, S.M. Wolff, and L. Chedid, Sleep-promoting effects of endogenous pyrogen (interleukin-1), Am. I. Physiol. 246:R994 (1984).Google Scholar
  26. 26.
    E.M. Friedman, S. Boinski, and C.E. Coe, Interleukin-1 induces sleep-like behavior and alters call structure in juvenile rhesus macaques, Am. J. Primatol. (in press).Google Scholar
  27. 27.
    C.A. Dinarello, Interleukin-1 and Interleukin-1 antagonism, Blood 8:1627 (1991).Google Scholar
  28. 28.
    J.M. Krueger, L. Kaṕas, M. Opp, and F. Ob́al Jr., Prostaglandins E2 and D2 have little effect on rabbit sleep, Physiol, and Behav. 51:481 (1992).CrossRefGoogle Scholar
  29. 29.
    M.R. Opp, F. Ob́al Jr., and J.M. Krueger, Effects of alpha-MSH on sleep, behavior, and brain temperature: interactions with IL1, Am. J. Physiol. 255:R914 (1988).Google Scholar
  30. 30.
    M. Opp, F. Ob́al Jr., and J.M. Krueger, Corticotropin-releasing factor attenuates interleukin-1 induced sleep and fever in rabbits, Am. J. Physiol. 257:R528 (1989).Google Scholar
  31. 31.
    M.R. Opp and J.M. Krueger, An interleukin-1 receptor antagonist blocks interleukin-1 induced sleep and fever, Am. J. Physiol. 260:R453 (1991).Google Scholar
  32. 32.
    M.R. Opp and J.M. Krueger, Effects of an interleukin-1 receptor antagonist on recovery sleep of rabbits after total sleep deprivation, Sleep Res. 20:416 (1991).Google Scholar
  33. 33.
    M. Opp and J.M. Krueger, Anti-interleukin-1b reduces sleep and sleep rebound after sleep deprivation in rats, Am. J. Physiol. (in press).Google Scholar
  34. 34.
    F. Ob́al Jr., M.R. Opp, A.B. Cady, L. Johannsen, A.E. Postlethwaite, H.M. Poppleton, J.M. Seyer, and J.M. Krueger, Interleukin-1 a and an interleukin-1b fragment are somnogenic, Am. J. Physiol. 259:R439 (1990).Google Scholar
  35. 35.
    M.R. Opp, A.E. Postlethwaite, J.M. Seyer, and J.M. Krueger, Interleukin-1 receptor antagonist blocks somnogenic and pyrogenic responses to an IL1 fragment, Proc. Natl. Acad. Sci. USA 89:3726 (1992).PubMedCrossRefGoogle Scholar
  36. 36.
    F. Berkenbosch, N. Robakis, and M. Blum, Interleukin-1 in the central nervous system: a role in the acute phase response and in brain injury, brain development and the pathogenesis of Alzheimer’s disease, in: Peripheral Signaling of the Brain, R.C.A. Frederickson et al., eds., Hogrefe & Hunter, Toronto (1991).Google Scholar
  37. 37.
    W.L. Farrar, J.M. Hill, A. Harel-Bellan, and M. Vinocour, The immune logical brain, Immunol. Rev. 100:361 (1987).PubMedCrossRefGoogle Scholar
  38. 38.
    W.L. Farrar, P.L. Kilan, M.R. Ruff, J.M. Hill, and C.B. Pert, Visualization and characterization of interleukin-1 receptors in brain, J. Immunol. 139:459 (1987).PubMedGoogle Scholar
  39. 39.
    F.G. Haour, E.M. Ban, G.M. Milon, D. Baran, G.M. Fillion, Brain interleukin-1 receptors: characterization and modulation after lipopolysaccharide injection, Prog. Neuro EndocrinImmunology 3:196 (1990).Google Scholar
  40. 40.
    C.D. Breder, C.A. Dinarello, C.B. Saper, Interleukin-1 immunoreactive innervation of the human hypothalamus, Science 240:321 (1988).PubMedCrossRefGoogle Scholar
  41. 41.
    R. Lechan, R. Toni, B. Clark, J. Cannon, A. Shaw, C.A. Dinarello, and S. Reichlin, Immunoreactive interleukin-1 beta localization in rat forebrain, Brain Res. 514:135 (1990).PubMedCrossRefGoogle Scholar
  42. 42.
    H. Moldofsky, FA. Lue, J. Eisen, E. Keystone, and R.M. Gorczynski, The relationship of interleukin-1 and immune functions to sleep in humans, Psychosom. Med. 48:309 (1989).Google Scholar
  43. 43.
    FA. Lue, M. Bail, J. Jephthah-Ocholo, K. Carayanniotis, R. Gorczynski, and H. Moldofsky, Sleep and cerebrospinal fluid interleukin-1 like activity in the cat, Intern. I. Neurosci. 42:179 (1988).CrossRefGoogle Scholar
  44. 44.
    S. Shoham, D. Davenne, A.B. Cady, C.A. Dinarello, and J.M. Krueger, Recombinant tumor necrosis factor and interleukin-1 enhance slow-wave sleep in rabbits, Am. J. Physiol. 253:R142 (1987).Google Scholar
  45. 45.
    L. Kapas and J.M. Krueger, Tumor necrosis factor b induces sleep, fever and and anorexia, Am. J. Physiol. 263:R703 (1992).Google Scholar
  46. 46.
    L. Kapas, L. Hong, A.B. Cady, M.R. Opp, A.E. Postlethwaite, J.M. Seyer, and J.M. Krueger, Somnogenic, pyrogenic and anorectic effects of TNFα fragments, Am. J. Physiol. 263:R708 (1992).Google Scholar
  47. 47.
    J. Vilcek and T.H. Lee, Tumor necrosis factor: New insights into the molecular mechanisms of its multiple actions, J. Biol. Chem. 266:7313 (1991).PubMedGoogle Scholar
  48. 48.
    C.D. Breder and C.B. Saper, Tumor necrosis factor immunoreactive innervation in the mouse brain, Soc. for Neurosci. Absts. 14:1280 (1988).Google Scholar
  49. 49.
    K. Yamasu, Y. Shimada, M. Sakaizumi, G.I. Soma, and D-I. Mizono, Activation of the systemic production of tumor necrosis factor after exposure to acute physical stress, Third Internat. Cont. on TNF and Related Cytokines Absts. 174 (1990).Google Scholar
  50. 50.
    J.M. Krueger, C.A. Dinarello, S. Shoham, D. Davenne, J. Walter, and S. Kubillus, Interferon alpha-2 enhances slow-wave sleep in rabbits, Int. Immunopharmacol. 9:23 (1987).CrossRefGoogle Scholar
  51. 51.
    M. Reite, M. Landenslager, J. Jones, C. Crnic, and K. Kaening, Interferon decreases REMS latency, Biol. Psychiatry 22:104 (1987).PubMedCrossRefGoogle Scholar
  52. 52.
    H. Smedlley, M. Katrak, K. Sikora, and T. Wheeler, Neurological effects of recombinant human interferon, Br. I. Med. 286:262 (1983).CrossRefGoogle Scholar
  53. 53.
    M. Kimura-Takeuchi, M.A. Majde, L.A. Toth, and J.M. Krueger, Influenza virus-induces changes in rabbit sleep and other acute phase responses, Am. J. Physiol. 263:R1115 (1992).Google Scholar
  54. 54.
    G.B. De Sarro, C. Ascioti, M.G. Audino, U. Rispoli, G. Nistico, Behavioral and ECOG spectrum changes induced by intracerebral microfusion of interferons and interleukin-2 in rats are antagonized by naloxone, in: Interactions among central nervous system, neuroendocrine and immune systems, J.W. Hadden et al., eds. Pythagona Press, Rome (1989).Google Scholar
  55. 55.
    J. Palmblad, K. Cantell, H. Strander, J. Froberg, C.G. Karlsson, L. Levi, M. Granstrom, and P. Unger, Stressor exposure and immunological response in man: interferon-producing capacity and phagocytosis, J. Psychosom. Res. 29:193 (1976).CrossRefGoogle Scholar
  56. 56.
    M. Opp, F. Ob́al, Jr., A.B. Cady, L. Johannsen, and J.M. Krueger, Interleukin-6 is pyrogenic but not somnogenic, Physiol. Behav. 45:1069 (1989).PubMedCrossRefGoogle Scholar
  57. 57.
    V. Rettori, J. Jurcovicova, and S.M. McCann, Central action of interleukin-1 in altering the release of TSH, growth hormone and prolactin in the male rat, J. Neurosci. Res. 18:179 (1987).PubMedCrossRefGoogle Scholar
  58. 58.
    L. Payne, F. Ob́al, Jr., M.R. Opp, J.M. Krueger, Stimulation and inhibition of growth hormone secretion by interleukin-1B: the involvement of GHRH, Neuroendocrinal. 56:118 (1992).CrossRefGoogle Scholar
  59. 59.
    F. Ob́al, Jr. and J.M. Krueger, Growth hormone-releasing hormone and interleukin-1 in sleep regulation, FASEB J. 7:645 (1993).PubMedGoogle Scholar
  60. 60.
    F. Ottal, Jr., M. Opp, G. Śary, and J.M. Krueger, Endocrine mechanisms in sleep regulation, in: Endogenous Sleep Factors, S. Inoue and J.M. Krueger, eds. The SPB Academic Publishing bv, Hague (1990).Google Scholar
  61. 61.
    D.J. McGinty, Physiological equilibrium and the control of sleep states, in: Brain Mechanisms of Sleep, D.J. McGirty et al., eds., Raven Press, New York (1985).Google Scholar
  62. 62.
    F. Ob́al, Jr., Effects of peptides (DSIP, DSIP analogues, VIP, GRF and CCK) on sleep in the rat, Clin. Neuropharmacol. 9:459 (1986).PubMedGoogle Scholar
  63. 63.
    F. Ob́al, Jr., P. Alf̈oldi, A.B. Cady, L. Johannsen, G. Śary, and J.M. Krueger, Growth hormone-releasing factor enhances sleep in rats and rabbits, Am. J. Physiol. 255:R310 (1988).Google Scholar
  64. 64.
    A. Steiger, J. Guldner, U. Hemmeter, B. Rothe, K. Wiedemann, F. Holsboer, Changes in sleep-EEG and nocturnal hormonal secretion under pulstile application of GHRH or somatostatin, Sleep Res. 20A:195 (1991).Google Scholar
  65. 65.
    F. Ob́al, Jr., L. Payne, L. Kapas, M. Opp, and J.M. Krueger, Inhibition of growth hormone-releasing factor suppresses both sleep and growth hormone secretion in the rat, Brain Res. 557:149 (1991).PubMedCrossRefGoogle Scholar
  66. 66.
    F. Ob́al, Jr., L. Payne, M. Opp, P. Alfoldi, L. Kaṕas, and J.M. Krueger, Antibodies to growth hormone-releasing hormone suppress sleep and prevent enhancement of sleep after sleep deprivation in the rat, Am. J. Physiol. 263:R1078 (1992).Google Scholar
  67. 67.
    R. Sapolsky, C. Rivier, G. Yamamoto, P. Plotsky, and W. Vale, Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor, Science 238:522 (1987).PubMedCrossRefGoogle Scholar
  68. 68.
    F. Berkenbosch, J. van Oers, A. Del Rey, F. Tilders, H. Besedovsky, Cortico-tropin-releasing factor-producing neurons in the rat activated by interleukin-1, Science 238:524 (1987).PubMedCrossRefGoogle Scholar
  69. 69.
    E.W. Bernton, J.E. Beach, J.W. Holaday, R.C. Smallridge, and H.G. Fein, Release of multiple hormones by a direct action of interleukin-1 on pituitary cells, Science 238:519 (1987).PubMedCrossRefGoogle Scholar
  70. 70.
    O. Hayaishi, Sleep-wake regulation by prostaglandin D2 and E2, J. Biol. Chem. 263:14593 (1988).PubMedGoogle Scholar
  71. 71.
    J. Garthwaite, Glutamate, nitric oxide and cell-cell signalling in the nervous system, Trends in Neuro. Sci. 14:60 (1991).CrossRefGoogle Scholar
  72. 72.
    L. Kaṕas, M. Shibata, and J.M. Krueger, Inhibition of nitric oxide synthesis suppresses sleep in rabbits, Am. J. Physiol, (in press).Google Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • James M. Krueger
    • 1
  • Linda Toth
    • 2
  1. 1.Departments of Physiology & BiophysicsUniversity of Tennessee, MemphisMemphisUSA
  2. 2.Departments of Comparative MedicineUniversity of TennesseeMemphisUSA

Personalised recommendations