Opposite effects of serotonin and interferon-α on the membrane potential and function of human natural killer cells

  • Tibor Oláh
  • Imre Ocsovszki
  • Yvette Mándi
  • Rozália Pusztai
  • Márta Bakay
  • Elisabeth Balint
Articles Cytokines/Growth Factors/Adhesion Factors


In an earlier article, we reported that serotonin (5-hydroxytryptamine, 5-HT) inhibits the natural killer cell (NK) cytotoxicity of human whole blood in a dose-dependent manner and that natural human interferon-α (IFN-α) partially eliminates this effect. Because natural IFN-α might contain factors other than IFN, we repeated these experiments with recombinant human interferon-α (rhIFN-α) and separated blood lymphocytes enriched with NK cells and then demonstrated that IFN really is responsible for this effect. Furthermore, this investigation was carried out to clarify the mechanisms of the action of 5-HT and of rhIFN-α on NK cells. The inhibition of the cytotoxicity was pronounced when 5-HT was added at the onset of the cytotoxic assay, whereas the pretreatment of lymphocytes for 18 h only led to a slight inhibition. Moreover, rhIFN-α applied 1 h before or 1 h after the addition of 5-HT decreased the inhibitory effect of 5-HT. Flow cytometric analysis involving the use of a voltage-sensitive dye, oxonol, revealed that 5-HT depolarized, whereas rhIFN-α hyperpolarized the plasma membrane of the lymphocytes. Thus, it seems likely that the inhibitory effect of 5-HT on the cytotoxicity of peripheral human lymphocytes is due to the depolarization on the plasma membrane of the effector cells and that rhIFN-α antagonizes this ability via its hyperpolarizing activity.

Key words

5-HT rhIFN-α eytotoxicity hyperpolarization depolarization 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Araneda, R.; Andrade, R. 5-hydroxytryptamine2 and 5-hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience 40:399–412; 1991.PubMedCrossRefGoogle Scholar
  2. Arzt, E. S.; Fernandez-Castcllo, S.; Finocchiaro, L. M. E.; Criscuolo, M. E.; Diaz, A.; Finkielman, A.; Nahmod, V. E. Immunomodulation by indoleamines: serotonin and melatonin action on DNA and interferon-γ synthesis by human peripheral blood mononuclear cells. J. Clin. Immunol. 8:513–520; 1988.PubMedCrossRefGoogle Scholar
  3. Balint, E.; Aszalos, A.; Pine, P. S.; Grimley, P. M. Dynamic analyses of lymphoblast membranes exposed to alpha interferon using flow cytometry and fluorescence recovery after photobleaching. Scanning Microsc. 2:2153–2163; 1988.PubMedGoogle Scholar
  4. Balint, E.; Cheng, M.; Rupp, B.; Grimley, M. P.; Aszalos, A. Cytoskeletal modulation of plasma membrane events induced by interferon-α. J. Interferon Res. 12:249–252; 1992.PubMedGoogle Scholar
  5. Basu, S.; Dasgupta, P. S. Dopamine, a neurotransmitter, influences the immune system. J. Neuroimmunol. 102:113–124; 2000.PubMedCrossRefGoogle Scholar
  6. Bearcroft, C. P.; Perrett, D.; Farthing, M. J. G. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 42:42–46; 1998.PubMedCrossRefGoogle Scholar
  7. Blaustein, R. O.; Miller, C. Shake, rattle or roll? Nature 427:499–500; 2004.PubMedCrossRefGoogle Scholar
  8. Böyum, A. Separation of leukocytes from blood and bone marrow. Scand. J. Clin. Lab. Invest. 21 (Suppl. 97):77–83; 1968.Google Scholar
  9. Cahalan, M. D.; Wulff, H.; Chandy, G. Molecular properties and physiological roles of ion channels in the immune system. J. Clin. Immunol. 21:235–252; 2001.PubMedCrossRefGoogle Scholar
  10. Gabrilovac, J.; Cicin-Sain, L.; Osmak, M.; Jerney, B. Alteration of NK- and ADCC-activities in rats genetically selected for low or high platelet serotonin level. J. Neuroimmunol. 37:213–222; 1992.PubMedCrossRefGoogle Scholar
  11. Garssadi, S. I.; Mándi, Y.; Régely, K.; Taródi, B.; Béládi, I. The inhibitory effect of interferon-alpha on the serotonin-induced impairment of human NK cell activity in whole blood. Brain Behav. Immun. 7:164–175; 1993.PubMedCrossRefGoogle Scholar
  12. Garssadi, S. I.; Régely, K.; Mándi, Y.; Béládi, I. Inhibition of cytotoxicity of chicken granulocytes by serotonin and ketanserin. Vet. Immunol. Immunopathol. 41:101–112; 1994.PubMedCrossRefGoogle Scholar
  13. Gudelsky, G. A.; Koenig, J. L.; Meltzer, H. Y. Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat: evidence for opposing roles of 5-HT2 and 5-HT1A receptors. Neuropharmacology 25:1307–1313; 1986.PubMedCrossRefGoogle Scholar
  14. Hellstrand, K.; Hermodsson, S. Role of serotonin in the regulation of human natural killer cell cytotoxicity. J. Immunol. 139:869–875; 1987.PubMedGoogle Scholar
  15. Hellstrand, K.; Hermodsson, S. Enhancement of human natural killer cell cytotoxicity by serotonin: role of non-T/CD16+ NK cells, accessory monocytes, and 5-HT1A receptors. Cell Immunol. 127:199–214; 1990.PubMedCrossRefGoogle Scholar
  16. Hess, S. D.; Oortgiesen, M.; Cahalan, M. D. Calcium oscillations in human T and natural killer cells depend upon membrane potential and calcium influx. J. Immunol. 150:2620–2633; 1993.PubMedGoogle Scholar
  17. Jackson, J. C.; Cross, R. J.; Walker, R. F.; Markesbery, W. R.; Brooks, W. H.; Roszman, T. L. Influence of serotonin on the immune response. Immunology 54:505–512; 1985.PubMedGoogle Scholar
  18. Kurachi, Y.; North, A. Ion channels: their structure, function, and control—an overview. J. Physiol. 554:245–247; 2003.CrossRefGoogle Scholar
  19. Levite, M. Nervous immunity: neurotransmitters extracellular K+ and T-cell function. Trends Immunol. 22:2–5; 2001.PubMedCrossRefGoogle Scholar
  20. Mandelboim, O.; Malik, P.; Davis, D. M.; Jo, C. H.; Boyson, J. E.; Strominger, J. L. Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity. Proc. Natl. Acad. Sci. USA 96:5640–5644; 1999.PubMedCrossRefGoogle Scholar
  21. Mándi, Y.; Garssadi, S. I.; Béládi, I. Comparison of roles of serine esterase in chicken and human natural cytotoxicity. Dev. Comp. Immunol. 14:113–119; 1990.PubMedCrossRefGoogle Scholar
  22. Mandler, R. N.; Seamer, L. C.; Domalewsky, M. D.; Bankhurst, A. D. Progesterone but not estrogen depolarizes natural killer cells. Nat. Immun. 12:128–135; 1993.PubMedGoogle Scholar
  23. Mandler, R. N.; Seamer, L. C.; Whitlinger, D.; Lennon, M.; Rosenberg, E.; Bankhurst, A. D. Human natural killer cells express Na+ channels (a pharmacologic flow cytometric study). J. Immunol. 144:2365–2370; 1990.PubMedGoogle Scholar
  24. Newberry, N. R.; Watkins, C. J.; Reynolds, D. J. M.; Leslie, R. A.; Grahame-Smith, D. G. Pharmacology of the 5-hydroxytryptamine-induced depolarization of the ferret vagus nerve in vitro. Eur. J. Pharmacol. 221:157–160; 1992.PubMedCrossRefGoogle Scholar
  25. Rothwell, N. J.; Hopkins, S. J. Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci. 18:130–136; 1995.PubMedCrossRefGoogle Scholar
  26. Schlichter, L. C. Acute exposure to human interferon-α affects ion currents in human natural killer cells. Can. J. Physiol. Pharmacol. 70:365–376; 1992.PubMedGoogle Scholar
  27. Stevens, D. R.; McCarley, R. W.; Greene, R. W. Serotonin1 and serotonin2 receptors hyperpolarize and depolarize separate populations of medial pontine reticular formation neurons in vitro. Neuroscience 47:545–552; 1992.PubMedCrossRefGoogle Scholar
  28. Takabayashi, A.; Kanai, M.; Kawai, Y.; Iwata, S.; Sasada, T.; Obama, K.; Taki, Y. Change in mitochondrial membrane potential in peripheral blood lymphocytes, especially in natural killer cells, is a possible marker for surgical stress on the immune system. World J. Surg. 27:659–665; 2003.PubMedCrossRefGoogle Scholar
  29. Wilson, H. A.; Chused, T. M. Lymphocyte membrane potential and Ca2+-sensitive potassium channels described by oxonol dye fluorescence measurements. J. Cell. Physiol. 125:72–81; 1985.PubMedCrossRefGoogle Scholar
  30. Yu, X.; Duan, K.-L.; Shang, C.-F.; Yu, H.-G. Zhou, Z. Calcium influx through hyperpolarization-activated cation channels (Ih channels) contributes to activity-evoked neuronal secretion. Proc. Natl. Acad. Sci. USA 101:1051–1056; 2004.PubMedCrossRefGoogle Scholar

Copyright information

© Society for In Vitro Biology 2005

Authors and Affiliations

  • Tibor Oláh
    • 1
  • Imre Ocsovszki
    • 2
  • Yvette Mándi
    • 3
  • Rozália Pusztai
    • 3
  • Márta Bakay
    • 3
  • Elisabeth Balint
    • 4
  1. 1.Surgical DepartmentTeaching HospitalSzegedHungary
  2. 2.Department of Biochemistry, Dóm tér 9University of SzegedSzegedHungary
  3. 3.Department of Medical Microbiology, Dóm tér 11University of SzegedSzegedHungary
  4. 4.Department of Optics and Quantum Electronics Dóm tér 9University of SzegedSzegedHungary

Personalised recommendations