Summary
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
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.
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.
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.
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.
Basu, S.; Dasgupta, P. S. Dopamine, a neurotransmitter, influences the immune system. J. Neuroimmunol. 102:113–124; 2000.
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.
Blaustein, R. O.; Miller, C. Shake, rattle or roll? Nature 427:499–500; 2004.
Böyum, A. Separation of leukocytes from blood and bone marrow. Scand. J. Clin. Lab. Invest. 21 (Suppl. 97):77–83; 1968.
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.
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.
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.
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.
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.
Hellstrand, K.; Hermodsson, S. Role of serotonin in the regulation of human natural killer cell cytotoxicity. J. Immunol. 139:869–875; 1987.
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.
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.
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.
Kurachi, Y.; North, A. Ion channels: their structure, function, and control—an overview. J. Physiol. 554:245–247; 2003.
Levite, M. Nervous immunity: neurotransmitters extracellular K+ and T-cell function. Trends Immunol. 22:2–5; 2001.
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.
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.
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.
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.
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.
Rothwell, N. J.; Hopkins, S. J. Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci. 18:130–136; 1995.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Oláh, T., Ocsovszki, I., Mándi, Y. et al. Opposite effects of serotonin and interferon-α on the membrane potential and function of human natural killer cells. In Vitro Cell.Dev.Biol.-Animal 41, 165–170 (2005). https://doi.org/10.1290/0407048.1
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1290/0407048.1