Skip to main content
SpringerLink
Log in

Neuroendocrine modulation of the immune system

Possible implications for inflammatory bowel disease

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Evidence for neuroendocrine regulation of the immune system is reviewed. This includes human clinical studies of the influence of psychological stress on immune function, direct experimentation in animals, including classical Pavlovian conditioning of the immune response, modulation of immune function in vitro by chemical messengers such as neuropeptides, the finding of receptors for neuropeptides on immunocytes, and the demonstration that lymphoid tissue is directly innervated. Secretory products of the immune system, which include interleukins and neuropeptides, may also influence the neuroendocrine system. Communication between the two systems is therefore bidirectional. The potential importance of the neuropeptide-immunocyte interaction within the intestinal mucosal immune system is emphasized, and its possible relevance in inflammatory disorders is discussed. This aspect of the “gut-brain” interaction deserves further study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Solomon GF, Amkraut AA: Psychoneuroendocrinological effects on the immune response. Annu Rev Microbiol 35:155–184, 1981

    PubMed  Google Scholar 

  2. Tecoma ES, Huey LY: Psychic distress and the immune response. Life Sci 36:1799–1812, 1985

    PubMed  Google Scholar 

  3. Locke S, Ader R, Besedovsky Hall N, Solomon G, Strom T, Spector NH (eds): Foundations of Psychoneuroimmunology. New York, Aldine Publishing, 1985

    Google Scholar 

  4. Ader R: Psychoneuroimmunology. London, Academic Press, 1981

    Google Scholar 

  5. Black S, Humphrey JH, Niven JSF: Inhibition of mantoux reaction by direct suggestion under hypnosis. Br Med J 6:1649–1952, 1965

    Google Scholar 

  6. Imboden JB, Canter A, Cluff LE: Convalescence from influenza. A study of the psychological and clinical determinants. Arch Intern Med 108:393–399, 1961

    PubMed  Google Scholar 

  7. Bartrop RW, Lazerus L, Luckhurst E, Kiloh LG, Penny R: Depressed lymphocyte function after bereavement. Lancet 1:834–836, 1977

    PubMed  Google Scholar 

  8. Schleifer SJ, Keller SE, Camerino E, Thornton JC, Stein M: Suppression of lymphocyte stimulation following bereavement. JAMA 250:374–378, 1983

    PubMed  Google Scholar 

  9. Stein M, Keller SE, Schleifer SJ: Stress and immunomodulation: The role of depression and neuroendocrine function. J Immunol 135:827s-833s, 1985

    PubMed  Google Scholar 

  10. Kiecolt-Glaser JK, Glaser R: Psychological influences on immunity. Psychosomatics 27:621–624, 1986

    PubMed  Google Scholar 

  11. Denman AM: Immunity and depression. Br Med J 293:464–465, 1986

    Google Scholar 

  12. Kiecolt-Glaser JK, Glaser R, Strain JC, Stout JC, Tarr KL, Holliday JE, Speicher CE: Modulation of cellular immunity in medical students. J Behav Med 9:5–21, 1986

    PubMed  Google Scholar 

  13. Kiecolt-Glaser JK, Glaser R, Stout JC, Tarr KL, Speicher CE, Holliday JE: Stress-related impairments in cellular immunity. Psychiatry Res 16:233–239, 1985

    PubMed  Google Scholar 

  14. Cohen JJ: Immunity and behavior. J Allergy Clin Immunol 79:2–5, 1987

    PubMed  Google Scholar 

  15. Pasteur L, Joubert J, Chamberland: Le charbon des poules. Compt Rend Acad Sci 87:47–48, 1878

    Google Scholar 

  16. Keller SE, Weiss JM, Schleifer SJ, Miller NE, Stein M: Suppression of immunity by stress: Effect of a graded series of stressors on lymphocyte stimulation in the rat. Science 213:1397–1399, 1981

    PubMed  Google Scholar 

  17. Monjan AA, Collector MI: Stress-induced modulation of the immune response. Science 196:307–308, 1977

    PubMed  Google Scholar 

  18. Shavit Y, Lewis JW, Terman GW, Gale RP, Liebeskind JC: Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity. Science 223:188–190, 1984

    PubMed  Google Scholar 

  19. Keller SE, Weiss JM, Schleifer SJ, Miller NE, Stein M: Stress induced immunosupression of immunity in adrenal-ectomized rats. Science 221:1301–1304, 1983

    PubMed  Google Scholar 

  20. Ader R, Cohen N, Bovjerg D: Immunoregulation by behavioral conditioning. Trends Pharmacol Sci 4:78–80, 1983

    Google Scholar 

  21. Rodgers MP, Reich P, Strom TB, Carpenter CB: Behaviorally conditioned immunosuppression: Replication of a recent study. Psychosomat Med 38:447–451, 1976

    Google Scholar 

  22. Wayner EA, Flannery GR, Singer G: Effects of taste aversion conditioning on the primary antibody response to sheep red blood cells andBrucella abortus in the albino rat. Physiol Behav 21:995–1000, 1978

    PubMed  Google Scholar 

  23. Russell M, Dark KA, Cummins RW, Ellman G, Callaway E, Peeke HVS: Learned histamine release. Science 225:733–734, 1984

    PubMed  Google Scholar 

  24. Ader R, Cohen N: Behaviorally conditioned immunosuppression and murine systemic lupus erythematous. Science 215:1534–1536, 1982

    PubMed  Google Scholar 

  25. Korneva EA, Khai LM: Effect of destruction of the hypothalamic areas on immunogenesis. Fiziol Zh SSSR 49:T88-T92, 1963

    Google Scholar 

  26. Jankovic BD, Isakovic K: Neuro-endocrine correlates of immune response. I. Effects of brain lesions on antibody production, arthus reactivity, and delayed hypersensitivity in the rat. Int Arch Allergy 45:360–372, 1973

    PubMed  Google Scholar 

  27. Brooks WH, Cross RJ, Roszman TL, Markesbery WR: Neuroimmunomodulation: Neural anatomical basis for impairment and facilitation. Ann Neurol 12:56–61, 1982

    PubMed  Google Scholar 

  28. Roszman TL, Brooks WH: Neural modulation of immune function. J Neuroimmunol 10:59–69, 1985

    PubMed  Google Scholar 

  29. Felten DL, Feiten SY, Carlson SL, Olschowka JA, Livnat S: Noradrenergic and peptidergic innervation of lymphoid. J Immunol 135:755s-765s, 1985

    PubMed  Google Scholar 

  30. Newson B, Dahlstrom A, Enerback L, Ahlman H: Suggestive evidence for a direct innervation of mucosal mast cells. Neuroscience 10:565, 1983

    PubMed  Google Scholar 

  31. Angeletti RH, Hickey WF: A neuroendocrine marker in tissues of the immune system. Science 230:89–90, 1985

    PubMed  Google Scholar 

  32. Stevenson HC, Fauci AS: Effects of corticosteroids on the function and distribution of human lymphocytes.In Clinical Immunology Update. EC Franklin (ed). New York, Elsevier, 1981, pp 337–355

    Google Scholar 

  33. Comsa J, Leonhardt H, Wekerle H: Hormonal coordination of the immune response. Rev Physiol Biochem Pharmacol 92:115–191, 1982

    PubMed  Google Scholar 

  34. Axelrod J, Reisine TD: Stress hormones: Their interaction and regulation. Science 224:452–459, 1984

    PubMed  Google Scholar 

  35. Ahmed SA, Penhale WJ, Talal N: Sex hormones, immune responses and autoimune diseases. Mechanism of sex hormone action. Am J Pathol 121:531–551, 1985

    PubMed  Google Scholar 

  36. Schleimer RP: The mechanisms of antiinflammatory steroid action in allergic diseases. Annu Rev Pharmacol Toxicol 25:381–412, 1985

    PubMed  Google Scholar 

  37. Mann JJ, Brown RP, Halper JP, Sweeney JA, Kocsis JH, Stokes PE, Bilezikian JP: Reduced sensitivity of lymphocyte beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. N Engl J Med 313:715–720, 1985

    PubMed  Google Scholar 

  38. Riley V: Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 212:1100–1109, 1981

    PubMed  Google Scholar 

  39. Payan DG, Brewster DR, Goetzl EJ: Specific stimulation of human T lymphocytes by substance P. J Immunol 131:1613–1615, 1983

    PubMed  Google Scholar 

  40. Stanisz AM, Befus D, Bienenstock J: Differential effects of vasoactive intestinal polypeptide, substance P, and somatostatin on immunoglobulin synthesis and proliferations by lymphocytes from Peyer's Patches, mesenteric lymph nodes, and spleen. J Immunol 136:152–156, 1986

    PubMed  Google Scholar 

  41. Ruff MR, Wahl SM, Pert CB: Substance P receptormediated chemotaxis of human monocytes. Peptides 6(suppl 2):107–111, 1985

    Google Scholar 

  42. Marasco WA, Showell HJ, Becker EL: Substance P binds to the formylpeptide chemotaxis receptor on the rabbit neutrophil. Biochem Biophys Res Commun 99:1065–1072, 1981

    PubMed  Google Scholar 

  43. Bar-Shavit Z, Goldman R, Stabinsky Y, Gottlieb P, Fridkin M, Teichberg VI, Blumberg S: Enhancement of phagocytosis—a newly found activity of substance P residing in itsN-terminal tetrapeptide sequence. Biochem Biophys Res Commun 94:1445–1450, 1980

    PubMed  Google Scholar 

  44. Shanahan F, Denburg JA, Fox J, Bienenstock J, Befus D: Mast cell heterogeneity: Effect of neuroenteric peptides on histamine release. J Immunol 135:1331–1337, 1985

    PubMed  Google Scholar 

  45. Foreman JC, Piotrowski W: Peptides and histamine release. J Allergy Clin Immunol 74:127–131, 1984

    PubMed  Google Scholar 

  46. Ottaway CA, Greenberg GR: Interaction of VIP with mouse lymphocytes: Specific binding and the modulation of mitogen responses. J Immunol 132:417–423, 1984

    PubMed  Google Scholar 

  47. Ottaway CA:In vitro alteration of receptors for vasoactive intestinal peptide changes thein vivo localization of mouse T cells. J Exp Med 160:1054–1069, 1984

    PubMed  Google Scholar 

  48. O'Dorisio MS, Hermina NS, O'Dorisio TM, Balcerzak SP: Vasoactive intestinal polypeptide modulation of lymphocyte adenylate cyclase. J Immunol 127:2551–2554, 1981

    PubMed  Google Scholar 

  49. Rola-Pleszcynski M, Bolduc D, St-Pierre S: The effects of VIP on human natural killer cells. J Immunol 135:2569–2573, 1985

    PubMed  Google Scholar 

  50. Goetzl EJ, Payan DG: Inhibition by somatostatin of the release of mediators from human basophils and rat leukemic basophils. J Immunol 133:3255–3259, 1984

    PubMed  Google Scholar 

  51. Gilman SC, Schwartz JM, Milner RJ, Bloom FE, Feldman JD: β-Endorphin enhances lymphocyte proliferative responses. Proc Natl Acad Sci USA 79:4226–4230, 1982

    PubMed  Google Scholar 

  52. McCain HW, Lamster IB, Buzzone JM, Grbic JT: β-Endorphin modulates human immune activity via non-opiate receptor mechanisms. Life Sci 31:1619–1624, 1982

    PubMed  Google Scholar 

  53. Mathews PM, Froelich CJ, Sibbit WL, Bankhurst AD: Enhancement of natural cytotoxicity by β-endorphin. J Immunol 130:1658–1662, 1983

    PubMed  Google Scholar 

  54. Johnson HM, Smith EM, Torres BA, Blalock JE: Regulation of thein vitro antibody response by neuroendocrine hormones. Proc Natl Acad Sci USA 79:4171–4173, 1982

    PubMed  Google Scholar 

  55. Snow EC, Feldbush TL, Oaks JA: The effect of growth hormone and insulin upon MLC responses and the generation of cytotoxic lymphocytes. J Immunol 126:161–164, 1981

    PubMed  Google Scholar 

  56. Payan DG, Brewster DR, Missirian-Bastien A, Goetzl EJ: Substance P recognition by a subset of human T lymphocytes. J Clin Invest 74:1532–1539, 1984

    PubMed  Google Scholar 

  57. Payan DG, McGillis JP, Organist ML: Characterization of the lymphocyte substance P receptor. J Biol Chem 261:14321–14329, 1986

    PubMed  Google Scholar 

  58. Hartung H-P, Wolters K, Toyka KV: Substance P: Binding properties and studies on cellular responses in guinea pig macrophages. J Immunol 136:3856–3863, 1986

    PubMed  Google Scholar 

  59. O'Dorisio MS: Biochemical characteristics of receptors for vasoactive intestinal polypeptide in nervous, endocrine, and immune systems. Fed Proc 46:192–195, 1987

    PubMed  Google Scholar 

  60. Wiik P, Opstad PK, Boyum A: Binding of vasoactive intestinal polypeptide (VIP) by human blood monocytes: Demonstration of specific binding sites. Regul Peptides 12:145–153, 1985

    Google Scholar 

  61. Bar-Shavit Z, Terry S, Blumberg S, Goldman R: Neurotensin-macrophage interaction: Specific binding and augmentation of phagocytosis. Neuropeptides 2:325–335, 1982

    Google Scholar 

  62. Bhathena SJ, Louie J, Schechter GP, Redman RS, Wahl L, Recant L: Identification of human mononuclear leukocytes bearing receptors for somatostatin and glucagon. Diabetes 30:127–131, 1981

    PubMed  Google Scholar 

  63. Lesniak MA, Gorden P, Roth J, Gavin JR: Binding of125I-human growth hormone to specific receptors in human cultured lymphocytes. J Biol Chem 249:1661–1667, 1974

    PubMed  Google Scholar 

  64. Pearse AGE, Polak JM, Bloom SR: The newer gut hormones. Cellular sources, physiology, pathology, and clinical aspects. Gastroenterology 72:746–761, 1977

    PubMed  Google Scholar 

  65. Gaginella TS, Mekhjian HS, O'Dorisio TM: Vasoactive intestinal peptide: Quantification by radioimmunoassay in isolated cells, mucosa, and muscle of the hamster intestine. Gastroenterology 74:718–721, 1978

    PubMed  Google Scholar 

  66. Morley JE: Food peptides. A new class of hormones? JAMA 247:2379–2380, 1982

    PubMed  Google Scholar 

  67. Bienenstock J, Befus AD: Mucosal immunology. Immunology 41:249–270, 1980

    PubMed  Google Scholar 

  68. Shanahan F, Lee TDG, Bienenstock J, Befus AD: The influence of endorphins on peritoneal and mucosal mast cell secretion. J Allergy Clin Immunol 74:499–504, 1984

    PubMed  Google Scholar 

  69. Goetzl EJ, Chernov-Rogan T, Furuichi K, Goetzl LM, Lee JY, Renold F: Neuromodulation of mast cell and basophil function.In Mast Cell Differentiation and Heterogeneity. AD Befus, J Bienenstock, JA Denburg (eds). New York, Raven Press, 1986, pp 223–229

    Google Scholar 

  70. Moore TC: Modification of lymphocyte traffic by vasoactive neurotransmitter substances. Immunology 52:511–518, 1984

    PubMed  Google Scholar 

  71. Besedovsky HO, Sorkin E, Felix D, Haas H: Hypothalamic changes during the immune response. Eur J Immunol 7:323–325, 1977

    PubMed  Google Scholar 

  72. Besedovsky H, Del Rey A, Sorkin E, Da Prada M, Burri R, Honegger C: The immune response evokes changes in brain noradrenergic neurons. Science 221:564–566, 1983

    PubMed  Google Scholar 

  73. Dinarello CA: Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med 311:1413–1418, 1984

    PubMed  Google Scholar 

  74. Hall NR, McGillis JP, Spangelo BL, Goldstein AL: Evidence that thymosins and other biologic response modifiers can function as neuroactive immunotransmitters. J Immunol 135:806s-811s, 1985

    PubMed  Google Scholar 

  75. Fontana A, Weber E, Dayer J-M: Synthesis of interleukin 1/endogenoiis pyrogen in the brain of endotoxin-treated mice: A step in fever induction? J Immunol 133:1696–1698, 1984

    PubMed  Google Scholar 

  76. O'Dorisio MS, O'Dorisio TM, Cataland S, Balcerzak SP: VIP as a biochemical marker for polymorphonuclear leukocytes. J Lab Clin Med 96:666–672, 1980

    PubMed  Google Scholar 

  77. Cutz E, Chan W, Track N, Goth A, Said S: Release of vasoactive intestinal polypeptide in mast cells by histamine liberators. Nature 275:661–662, 1978

    PubMed  Google Scholar 

  78. Goetzl EJ, Chernov-Rogan T, Cooke MP, Renold F, Payan DG: Endogenous somatostatin-like peptides of rat basophilic leukemia cells. J Immunol 135:2707–2712, 1985

    PubMed  Google Scholar 

  79. Smith EM, Blalock JE: Human lymphocyte production of corticotropin and endorphin-like substances: Association with leukocyte interferon. Proc Natl Acad Sci USA 78:7530–7534, 1981

    PubMed  Google Scholar 

  80. Lolait SJ, Lim ATW, Toh BH, Funder JW: Immunoreactive β-endorphin in a subpopulation of mouse spleen macrophages. J Clin Invest 73:277–280, 1984

    PubMed  Google Scholar 

  81. Smith EM, Phan M, Kruger TE, Coppenhaver DH, Blalock JE: Human lymphocyte production of immunoreactive thyrotropin. Proc Natl Acad Sci USA 80:6010–6013, 1983

    PubMed  Google Scholar 

  82. Blalock JE, Bost KL, Smith EM: Neuroendocrine peptide hormones and their receptors in the immune system. J Neuroimmunol 10:31–40, 1985

    Google Scholar 

  83. Roth J, LeRoith D, Shiloach J, Rosenzweig JL, Lesniak MA, Havrankova J: The evolutionary origins of hormones, neurotransmitters, and other extracellular chemical messengers. Implications for mammalian biology. N Engl J Med 306:523–527, 1982

    PubMed  Google Scholar 

  84. LeRoith D, Shiloach J, Berelowithz M, Frohman LA, Liotta AS, Krieger DT, Roth J: Are messenger molecules in microbes the ancestors of the vertebrate hormones and tissue factors? Fed Proc 42:2602–2607, 1983

    PubMed  Google Scholar 

  85. Schmitt FO: Molecular regulators of brain function: a new view. Neuroscience 13:991–1001, 1984

    PubMed  Google Scholar 

  86. Blalock JE: Relationships between neuroendocrine hormones and lymphokines. Lymphokines 9:1–13, 1984

    Google Scholar 

  87. Gurney ME, Heinrich SP, Lee MR, Yin H-S: Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons. Science 234:566–574, 1986

    PubMed  Google Scholar 

  88. Gurney ME, Apatoff BR, Spear GT, Baumel MJ, Antel JP, Brown Bania M, Reder AT: Neuroleukin: A lymphokine product of lectin-stimulated T cells. Science 234:574–581, 1986

    PubMed  Google Scholar 

  89. Blalock JE: The immune system as a sensory organ. J Immunol 132:1067–1070, 1984

    PubMed  Google Scholar 

  90. Strober W, James SP: The immunologic basis of inflammatory bowel disease. J Clin Immunol 6:415–432, 1986

    PubMed  Google Scholar 

  91. Shanahan F: Inflammatory bowel disease.In Immunology of Intestinal Disease. SR Targan (moderator). Ann Intern Med 106:862–866, 1987

    Google Scholar 

  92. Levine JD, Clark R, Devor M, Helms C, Moskowitz MA, Basbaum AL: Interneuronal substance P contributes to the severity of experimental arthritis. Science 226:547–549, 1984

    PubMed  Google Scholar 

  93. Levine JD, Moskowitz MA, Basbaum AL: The contribution of neurogenic inflammation in experimental arthritis. J Immunol 135:843s-847s, 1985

    PubMed  Google Scholar 

  94. Lembeck F, Donnerer J, Colpaert FC: Increase in substance P in primary afferent nerves during chronic pain. Neuropeptides 1:175–180, 1981

    Google Scholar 

  95. Kyosola K, Penttila O, Salaspuro M: Rectal mucosal adrenergic innervation and enterochromaffin cells in ulcerative colitis and irritable colon. Scand J Gastroenterol 12:363–367, 1977

    PubMed  Google Scholar 

  96. Morson BC, Dawson IMP: Inflammatory disorders.In Gastrointestinal Pathology. BC Morson, IMP Dawson (eds). Oxford, Blackwell Scientific, 1972, pp 243–298

    Google Scholar 

  97. Davis DR, Dockerty MB, Mayo CW: The myenteric plexus in regional enteritis; a study of 24 cases. Surg Gynecol Obstet 101:208, 1955

    PubMed  Google Scholar 

  98. Bishop AE, Polak JM, Bryant MG, Bloom SR, Hamilton S: Abnormalities of vasoactive intestinal polypeptide-containing nerves in Crohn's disease. Gastroenterology 79:853–860, 1980

    PubMed  Google Scholar 

  99. Dawson J, Bryant MG, Bloom SR, Peters TJ: Gastrointestinal regulatory peptide storage granule abnormalities in jejunal mucosal diseases. Gut 25:636–643, 1984

    PubMed  Google Scholar 

  100. Anton P, Durham M, Schwabe A, Targan S, Shanahan F: Enhanced sensitivity of neutrophils to f-Met-Leu-Phe in familial Mediterannean fever. J Clin Immunol 1988 (in press)

  101. Castro GA: Immunological regulation of epithelial function. Am J Physiol 243:(Gastrointest Liver Physiol 6):G321-G329, 1982

    PubMed  Google Scholar 

  102. Payan DG, McGillis JP, Goetzl EJ: Neuroimmunology. Adv Immunol 39:299–323, 1986

    PubMed  Google Scholar 

  103. O'Dorisio MS: Neuropeptides and gastrointestinal immunity. Am J Med 81(suppl 6B):74–82, 1986

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Harbor/UCLA Inflammatory Bowel Disease Center, USA

    Fergus Shanahan MD & Peter Anton MD

  2. Department of Medicine, Division of Gastroenterology, UCLA School of Medicine, Center for the Health Sciences, 10833 Le Conte Avenue, 90024, Los Angeles, CA

    Fergus Shanahan MD & Peter Anton MD

Authors
  1. Fergus Shanahan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Anton MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported by the Harbor/UCLA Inflammatory Bowel Disease NIH Center grant AM 36200 and the Blinder Crohn's Disease Research Foundation. Dr. Shanahan is a recipient of a career development award from the National Foundation for Ileitis and Colitis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shanahan, F., Anton, P. Neuroendocrine modulation of the immune system. Digest Dis Sci 33 (Suppl 3), 41S–49S (1988). https://doi.org/10.1007/BF01538130

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01538130

Keywords

Search

Navigation