Mechanisms of the Behavioural Effects of Cytokines

  • Robert Dantzer
  • Arnaud Aubert
  • Rose-Marie Bluthé
  • Gilles Gheusi
  • Sandrine Cremona
  • Sophie Layé
  • Jan-Pieter Konsman
  • Patricia Parnet
  • Keith W. Kelley
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 461)


Sickness behavior refers to the coordinated set of behavioral changes that develop in sick individuals during the course of an infection. A sick individual typically displays depressed locomotor activity and little or no interest in his physical and social environment. Body care activities are usually absent and ingestive behavior is profoundly depressed despite the increased metabolism that is necessary for the fever response. Since the initial demonstration in the late eighties that similar symptoms are induced in healthy subjects by peripheral and central injection of the proinflammatory cytokines that are released by activated monocytes and macrophages during the host response to infection, the mechanisms of cytokine-induced sickness behaviour have been the subject of intense research, carried out at several levels of investigation. The purpose of the present chapter is to review the results that have been obtained in this field during the last decade. At the behavioural level, there is now clear evidence showing that sickness behaviour is not the result of weakness and physical debilitation affecting the sick individual, but the expression of a central motivational state that reorganizes the organism’s priorities to cope with pathogenic microorganisms. At the organ level, this motivational aspect of sickness behavior is important since it implies that the endogenous signals of sickness are likely to act on the brain to activate a set of neural structures that are at the origin of the subjective, behavioural and physiological components of sickness. The presence of cytokine receptors in the brain is in accordance with this view.


Reverse Transcription Polymerase Chain Reaction Depressing Effect Sickness Behaviour Medial Preoptic Area Circumventricular Organ 
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. Aubert, A., Goodall, G., Dantzer, R., & Gheusi, G. (1997a). Differential effects of lipopolysaccharide on pup retrieving and nest building in lactating mice. Brain Behavior & Immunity, 11, 107–118.CrossRefGoogle Scholar
  2. Aubert, A., Kelley, K. W., & Dantzer, R. (1997b). Differential effect of lipopolysaccharide on food hoarding behavior and food consumption in rats. Brain, Behavior, & Immunity, 11, 229–238.CrossRefGoogle Scholar
  3. Ban, E., Marquette, C., Sarrieau, A., Fitzpatrick, F., Fillion, G., Millon, G., Rostène, W., & Haour, F. (1993). Regulation of interleukin-1 receptor expression in mouse brain and pituitary by lipopolysaccharide and glucocorticoids. Neuroendocrinology, 58, 581–587.PubMedGoogle Scholar
  4. Banks, W. A., Ortiz, L., Plotkin, S. R., & Kastin, A. J. (1991). Human interleukin (IL) 1 alpha, murine IL-1 alpha, and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism. Journal of Pharmacology and Experimental Therapeutics, 259, 988–996.PubMedGoogle Scholar
  5. Baura, G. D., Foster, D. M., Porte, D. Jr., Kahn, S. E., Bergman, R. N., Cobelli, C., & Schwartz, M. W. (1993). Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. Journal of Clinical Investigation, 92, 1824–1830.PubMedCrossRefGoogle Scholar
  6. Bertini, R., Bianchi, M., & Ghezzi, P. (1988) Adrenalectomy sensitizes mice to lethal effects of interleukin-1 and tumor necrosis factor. Journal of Experimental Medicine, 167, 1708–1712.PubMedCrossRefGoogle Scholar
  7. Besedovsky, H. O., del Rey, A., Sorkin, E., & Dinarello, C. A. (1986). Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science, 233, 652–654.PubMedCrossRefGoogle Scholar
  8. Betancur, C., Lledo, A., Borrell, J., & Guaza, C. (1994). Corticosteroid regulation of IL-1 receptors in the mouse hippocampus: effects of glucocorticoid treatment, stress, and adrenalectomy. Neuroendocrinology, 59, 120–128.PubMedGoogle Scholar
  9. Blatteis, C. M. (1990). Neuromodulative actions of cytokines. Yale Journal of Biological Medicine, 63, 133–142.Google Scholar
  10. Bluthé, R. M., Dantzer, R., & Kelley, K. W. (1992). Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Research, 573, 318–320.PubMedCrossRefGoogle Scholar
  11. Bluthé, R. M., Walter, V., Parnet, P., Layé, S., Lestage, J., Verrier, D., Poole, S., Stenning, B. E., Kelley, K. W., & Dantzer, R. (1994) Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. Comptes Rendus de l’Académie des Science (Paris), 317, 499–503.Google Scholar
  12. Bluthé, R. M., Michaud, B., Kelley, K. W., & Dantzer, R. (1996a). Vagotomy blocks behavioural effects of interleukin-1 injected via the intraperitoneal route but not via other systemic routes. NeuroReport, 7, 2823–2827.PubMedCrossRefGoogle Scholar
  13. Bluthé, R. M., Michaud, B., Kelley, K. W., & Dantzer, R. (1996b). Vagotomy attenuates behavioral effects of interleukin-1 injected peripherally but not centrally. NeuroReport, 7, 1485–1488.PubMedCrossRefGoogle Scholar
  14. Bluthé, R. M., Michaud, B., Dantzer, R., & Kelley, K. W. (1997). Central mediation of the effects of interleukin-1 on social exploration and body weight in mice. Psychoneuroendocrinology, 22, 1–11.PubMedCrossRefGoogle Scholar
  15. Bolles, R. C. (1970). Species-specific defense reactions and avoidance learning. Psychological Review, 77, 32–48.CrossRefGoogle Scholar
  16. Breder, C. D. & Saper, C. B. (1996). Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. Brain Research, 713, 64–69.PubMedCrossRefGoogle Scholar
  17. Breder, C. D., Hazuka, C., Ghayur, T., Klug, C., Huginin, M., Yasuda, K., Teno, M., & Saper, C. B. (1994). Regional induction of tumor necrosis factor a expression in the mouse brain after systemic lipopolysaccharide administration. Proceedings of the National Academy of Sciences USA, 91, 11393–11397.CrossRefGoogle Scholar
  18. Bret-Dibat, J. L., Bluthé, R. M., Kent, S., Kelley, K. W., & Dantzer, R. (1995). Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain, Behavior, & Immunity, 9, 242–246.CrossRefGoogle Scholar
  19. Bristulf, J., Gatti, S., Malinowsky, D., Bjork, L., Sundgren, A. K., & Bartfai, T. (1994). Interleukin-1 stimulates the expression of type I and type II interleukin-1 receptors in the rat insulinoma cell line Rinm5F: sequencing a rat type II interleukin-1 receptor cDNA. European Cytokine Network, 5, 319–330.PubMedGoogle Scholar
  20. Burgess, W., Gheusi, G., Yao, J., Johnson, R. W., Dantzer, R., & Kelley, K. W. (1998). Interleukin-lβ converting enzyme (ICE)-deficient mice are resistant to central but not systemic lipopolysaccharide-induced aphagia. American Journal of Physiology, 274, R1829–R1833.PubMedGoogle Scholar
  21. Buttini, M. & Boddeke, H. (1995). Peripheral lipopolysaccharide stimulation induces interleukin-lβ messenger RNA in rat brain microglial cells. Neuroscience, 65, 523–530.PubMedCrossRefGoogle Scholar
  22. Cao, C. Y., Matsumura, K., Yamagata, K., & Watanabe, Y. (1996). Endothelial cells of the rat-brain vasculature express cyclooxygenase-2 messenger-RNA in response to systemic interleukin-1: a possible site of prostaglandin synthesis responsible for fever. Brain Research, 733, 263–272.PubMedCrossRefGoogle Scholar
  23. Coehlo, M. M., Souza, G. E. P., & Pela, I. R. (1982). Endotoxin-induced fever is modulated by endogenous glucocorticoids in rats. American Journal of Physiology, 263, R423–R427.Google Scholar
  24. Cremona S., Goujon, E., Kelley, K. W., Dantzer, R., & Parnet, P. (1998). Brain type I but not type II interleukin-1 (IL-1) receptors mediate the effects of IL-lβ on behavior in mice. American Journal of Physiology, 274, R735–R740.PubMedGoogle Scholar
  25. Dantzer, R. (1994). How do cytokines say hello to the brain? Neural versus humoral mediation. European Cytokine Network, 5, 271–273.PubMedGoogle Scholar
  26. Dantzer, R. & Kelley, K. W. (1989). Stress and immunity: An integrated view of relationships between the brain and the immune system. Life Sciences, 44, 1995–2008.PubMedCrossRefGoogle Scholar
  27. Dantzer R., Bluthé, R. M., & Kelley, K. W. (1991). Androgen-dependent vasopressinergic neurotransmission attenuates interleukin-1-induced sickness behavior. Brain Research, 557, 115–120.PubMedCrossRefGoogle Scholar
  28. Dinarello, C. A. (1996). Biologic basis for interleukin-1 in disease. Blood, 87, 2095–2147.PubMedGoogle Scholar
  29. Elmquist, J. K., Scammell, T. E., & Saper, C. B. (1997). Mechanisms of CNS response to systemic immune challenge: the febrile response. Trends in Neuroscience, 20, 565–570.CrossRefGoogle Scholar
  30. Ericsson, A., Kovacs, K. J., & Sawchenko, P. E. (1994). A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. Journal of Neuroscience, 14, 897–913.PubMedGoogle Scholar
  31. Ericsson, A., Liu, C., Hart, R. P., & Sawchenko, P. E. (1995). Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1 induced cellular activation. Journal of Comparative Neurology, 361, 681–698.PubMedCrossRefGoogle Scholar
  32. Gatti, S. & Bartfai, T. (1993). Induction of tumor necrosis factor a mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Research, 624, 291–295.PubMedCrossRefGoogle Scholar
  33. Goujon, E., Parnet, P., Aubert, A., Goodall, G., & Dantzer, R. (1995a). Corticosterone regulates behavioral effects of lipopolysaccharide and interleukin-lβ in mice. American Journal of Physiology, 269, R154–R159.PubMedGoogle Scholar
  34. Goujon, E., Parnet, P., Crémona, S., & Dantzer, R. (1995b). Endogenous glucocorticoids downregulate central effects of interleukin-lβ on body temperature and behavior in mice. Brain Research, 702, 173–180.PubMedCrossRefGoogle Scholar
  35. Goujon, E., Parnet, P., Layé, S., Combe, C., Kelley, K. W., & Dantzer, R. (1995c). Stress downregulates lipopolysaccharide-induced expression of proinflammatory cytokines in the spleen, pituitary and brain of mice. Brain, Behavior, & Immunity, 9, 292–303.CrossRefGoogle Scholar
  36. Goujon, E., Parnet, P., Layé, S., Combe, C., & Dantzer, R. (1996). Adrenalectomy enhances proinflammatory cytokine gene expression in the spleen, pituitary and brain of mice in response to lipopolysaccharide. Molecular Brain Research, 36, 53–62.PubMedCrossRefGoogle Scholar
  37. Greenfeder, S. A., Nunes, P., Kwee, L., Labow, M., Chizzonite, R. A., & Ju, G. (1995). Molecular cloning and characterization of a second subunit of the interleukin-1 receptor complex. Journal of Biological Chemistry, 270, 13757–13765.PubMedCrossRefGoogle Scholar
  38. Hansen, M. K., Taishi, P., Chen, Z., & Krueger, J. M. (1998). Vagotomy blocks the induction of interleukin-1β (IL-1β) mRNA in the brain of rats in response to systemic IL-1β. Journal of Neuroscience, 18, 2247–2253.PubMedGoogle Scholar
  39. Haour, F. G., Ban, E. M., Milon, G. M., Baran, D., & Fillion G. M. (1990). Brain interleukin-1 receptors. Characterization and modulation after lipopolysaccharide injection. Progress in NeuroEndocrino-Immunology, 3, 196–204.Google Scholar
  40. Hart, B. L. (1988). Biological basis of the behavior of sick animals. Neuroscience & Biobehavioral Reviews, 12, 123–137.CrossRefGoogle Scholar
  41. Hopkins, S. J. & Rothwell, N. J. (1995). Cytokines and the nervous system. I: Expression and recognition. Trends in Neurosciences, 18, 83–87.PubMedCrossRefGoogle Scholar
  42. Kakucska, I., Qi, Y., Clark, B. D., & Lechan, R. M. (1993). Endotoxin-induced corticotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is mediated centrally by interleukin-1. Endocrinology, 133, 815–821.PubMedCrossRefGoogle Scholar
  43. Kent S., Bluthé, R. M., Dantzer, R., Hardwick, A. J., Kelley, K. W., Rothwell, N. J., & Vannice, J. L. (1992a). Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin-1. Proceedings of the National Academy of Sciences USA, 89, 9117–9120.CrossRefGoogle Scholar
  44. Kent, S., Bluthé, R. M., Kelley, K. W., & Dantzer, R. (1992b). Sickness behavior as a new target for drug development. Trends in Pharmacological Sciences, 13, 24–28.PubMedCrossRefGoogle Scholar
  45. Kent, S., Kelley, K. W., & Dantzer, R. (1992c). Effects of lipopolysaccharide on food-motivated behavior are not blocked by an interleukin-1 receptor antagonist. Neuroscience Letters, 145, 83–86.PubMedCrossRefGoogle Scholar
  46. Kent, S., Bret-Dibat, J. L., Kelley, K. W., & Dantzer, R. (1996). Mechanisms of sickness-induced decreases in food-motivated behavior. Neuroscience & Biobehavioral Reviews, 20, 171–175.CrossRefGoogle Scholar
  47. Klir, J. J., McClellan, J. L., & Kluger, M. J. (1994). Interleukin-1β causes the increase in anterior hypothalamic interleukin-6 during LPS-induced fever in rats. American Journal of Physiology, 266, R1845–R1848.PubMedGoogle Scholar
  48. Kluger, M. J. (1991). Fever: Role of pyrogens and cryogens. Physiological Reviews, 71, 93–127.PubMedGoogle Scholar
  49. Konsman, J. P., Kelley, K. W., & Dantzer, R. (1998). Temporal and spatial relationships between lipopoly-saccharide-induced expression of Fos, interleukin-1β and inducible NO synthase in rat brain. Neuroscience, L89, 535–548.Google Scholar
  50. Lacroix, S. & Rivest, S. (1998). Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cycloxygenase enzymes (COX-1 and COX-2) in the rat brain. Journal of Neurochemistry, 70, 452–66.PubMedCrossRefGoogle Scholar
  51. Layé, S., Parnet, P., Goujon, E., & Dantzer, R. (1994). Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. Molecular Brain Research, 27, 157–162.PubMedCrossRefGoogle Scholar
  52. Layé S., Bluthé, R. M., Kent, S., Combe, C., Médina, C., Parnet, P., Kelley, K. W., & Dantzer, R. (1995). Subdiaphragmatic vagotomy blocks induction of IL-lβ mRNA in mice brain in response to peripheral LPS. American Journal of Physiology, 268, R1327–R1331.PubMedGoogle Scholar
  53. Layé, S., Goujon, E., Combe, C., VanHoy, R., Kelley K. W., Parnet, P., & Dantzer, R. (1996). Effects of lipopolysaccharide and glucocorticoids on expression of interleukin-1β converting enzyme in the pituitary and brain of mice. Journal of Neuroimmunology, 68, 61–66.PubMedCrossRefGoogle Scholar
  54. Lee, S. W., Tsou, A. P., Chan, H., Thomas, J., Petrie, K., Eugui, E. M., & Allison, C. A. (1988). Glucocorticoids selectively inhibit the transcription of the interleukin-1β gene and decrease the stability of interleukin-1β mRNA. Proceedings of the National Academy of Sciences USA, 85, 1204–1208.CrossRefGoogle Scholar
  55. Le May, L. G., Vander, A. J., & Kluger, M. J. (1990). The effect of psychological stress on plasma interleukin-6 activity in rats. Physiology & Behavior, 47, 957–961.CrossRefGoogle Scholar
  56. McClellan, J. L., Klir, J. J., Morrow, L. E., & Kluger, M. J. (1994). Central effects of glucocorticoid receptor antagonist RU-38486 on lipopolysacharide and stress-induced fever. American Journal of Physiology, 267, R705–R711.PubMedGoogle Scholar
  57. Miller, N. E. (1964). Some psychophysiological studies of motivation and of the behavioral effects of illness. Bulletin of the British Psychology Society, 17, 1–20.Google Scholar
  58. Minami, M., Kuraishi, Y., Yamaguchi, T., Nakai, S., Hirai, Y., & Satoh, M. (1991). Immobilization stress induces interleukin-1 beta mRNA in the hypothalamus. Neuroscience Letters, 123, 254–256.PubMedCrossRefGoogle Scholar
  59. Morrow, L. E., McClellan, J. L., Conn, C. A., & Kluger M. J. (1993). Glucocorticoids alter fever and IL-6 responses to psychological stress and to lipopolysaccharide. American Journal of Physiology, 264, R1010–R1016.PubMedGoogle Scholar
  60. Nicola, N. A. (ed) (1994). Guidebook to cytokines and their receptors. Oxford University Press, Oxford.Google Scholar
  61. Parnet P., Amindari, S., Wu, C., Brunke-Reese, D., Goujon, E., Weyhenmeyer, J. A., Dantzer, R., & Kelley, K. W. (1994). Expression of type I and type II interleukin-1 receptors in mouse brain. Molecular Brain Research, 27, 63–70.PubMedCrossRefGoogle Scholar
  62. Plata-Salaman, C. R. (1995). Cytokines and feeding suppression: An integrative view from neurological to molecular levels. Nutrition, 11, 674–677.PubMedGoogle Scholar
  63. Plata-Salaman, C. R. (1997). Anorexia during acute and chronic disease. Relevance of neurotransmitter-peptide-cytokine interactions. Nutrition, 13, 159–160.PubMedCrossRefGoogle Scholar
  64. Plata-Salaman, C. R., Oomura, Y., & Kai, Y. (1988). Tumor necrosis factor and interleukin-1β suppression of food intake by direct action in the central nervous system. Brain Research, 448, 106–114.PubMedCrossRefGoogle Scholar
  65. Quan, N., Whiteside, M., Kim, L., & Herkenham, M. (1997). Induction of inhibitory factor kappaBalpha mRNA in the central nervous system after peripheral lipopolysaccharide administration: an in situ hybridization histochemistry study in the rat. Proceedings of the National Acdemy of Sciences USA, 94, 10985–10990.CrossRefGoogle Scholar
  66. Rachamandra, R. N., Sehon A. H., & Berczi, I. (1992). Neuro-hormonal host defence in endotoxin shock. Brain, Behavior & Immunity, 6, 157–169.CrossRefGoogle Scholar
  67. Satta, M. A., Jacobs, R. A., Kaltsas, G. A., & Grossman, A. B. (1998). Endotoxin induces interleukin-1β and nitric oxide synthase mRNA in rat hypothalamus and pituitary. Neuroendocrinology, 67, 109–116.PubMedCrossRefGoogle Scholar
  68. Schöbitz, B., de Kloet, E. R., & Holsboer, F. (1994). Gene expression and function of interleukin 1, inter-leukin 6 and tumor necrosis factor in the brain. Progress in Neurobiology, 44, 397–432.PubMedCrossRefGoogle Scholar
  69. Takao, T., Tracey, D. E., Mitchell, W. M., & De Souza, E. B. (1991). Interleukin-1 receptors in mouse brain: characterization and neuronal localization. Endocrinology, 127, 3070–3078.CrossRefGoogle Scholar
  70. Van Dam A. M., Brouns, M., Louisse, S., & Berkenbosch, F. (1992). Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness. Brain Research, 588, 291–296.PubMedCrossRefGoogle Scholar
  71. Wan, W., Wetmore, W., Sorensen, C. M., Greenberg, A. H., & Nance, D. M. (1994). Neural and biochemical mediators of endotoxin and stress-induced c-fos expression in the rat brain. Brain Research Bulletin, 34, 7–14.PubMedCrossRefGoogle Scholar
  72. Watkins, L. R., Maier, S. F., & Goehler, L. E. (1995). Cytokine-to-brain communication: A review & analysis of alternative mechanisms. Life Sciences, 57, 1011–1026.PubMedCrossRefGoogle Scholar
  73. Wong, M. L., Bongiorno, P. B., Rettori, V., McCann, S. M., & Licinio, J. (1997). Interleukin (IL)1β, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications. Proceedings of the National Academy of Sciences USA, 94, 227–232.CrossRefGoogle Scholar
  74. Wong, M. L., Rettori, V., Al-Shekhlee, A., Bongiorno, P. B., Canteros, G., McCann, S. M., Gold, P. W., & Licinio, J. (1996). Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Nature Medicine, 2, 581–584.PubMedCrossRefGoogle Scholar
  75. Wu, D., Yang, J., & Pardridge, W. M. (1997). Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor. Journal of Clinical Investigation, 100, 1804–1812.PubMedGoogle Scholar
  76. Zhou, D., Kusnecov, A. W, Shurin, M. R., DePaoli, M., & Rabin, B. S. (1993). Exposure to physical and psychological Stressors elevates plasma interleukin-6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology, 133, 2523–2530.PubMedCrossRefGoogle Scholar
  77. Zuckerman, S. H., Shellhaas, J., & Butler, L. D. (1989). Differential regulation of lipopolysacharide-induced interleukin-1 and tumor necrosis factor synthesis: effects of endogenous glucocorticoids and the role of pituitary-adrenal axis. European Journal of Immunology, 19, 301–305.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic/Plenum Publishers 1999

Authors and Affiliations

  • Robert Dantzer
    • 1
  • Arnaud Aubert
    • 1
  • Rose-Marie Bluthé
    • 1
  • Gilles Gheusi
    • 1
  • Sandrine Cremona
    • 1
  • Sophie Layé
    • 1
  • Jan-Pieter Konsman
    • 1
  • Patricia Parnet
    • 1
  • Keith W. Kelley
    • 2
  1. 1.Neurobiologie intégrativeINRA-INSERMBordeaux CedexFrance
  2. 2.Laboratory of Immunophysiology, Department of Animal SciencesUniversity of IllinoisUrbana

Personalised recommendations