Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-γ and interleukin-10

Serotonin (5-HT) is a neurotransmitter and an immune modulator. In vitro, antidepressants with a serotonergic mode of action have, at concentrations within the therapeutical range, negative immunoregulatory effects, i.e., they increase the production rate of interleukin-10 (IL-10), a negative immunoregulatory cytokine. We have hypothesized that part of these effects may by explained by the serotonergic activities of antidepressants on immunocytes. This study was carried out to examine the effects of 5-HT, p-chlorophenylalanine (PCPA), a 5-HT depleting agent, flesinoxan (a 5-HT1A agonist), m-chlorophenylpiperazine (mCPP; a 5-HT2A/2C agonist), and ritanserin (a 5-HT2A/2C antagonist) on the production rate of interferon-gamma (IFN gamma), a proinflammatory cytokine, and IL-10 by whole blood stimulated with polyclonal activators. The IFN gamma/IL-10 production ratio was computed since this ratio reflects the pro- versus anti-inflammatory capacity of cultured whole blood. We found that: 1) 5-HT, 150 ng/mL, 1.5 mu g/mL, and 15 mu g/mL significantly decreased the IFN gamma/IL-10 ratio; 2) PCPA (5 mu M) significantly suppressed the production of IFN gamma and IL-10; 3) flesinoxan (15 ng/mL; 1.5 mu g/mL) had no significant effects on the production of the above cytokines; and 4) mCPP (2.7 mu g/mL) and ritanserin (5.0 mu g/mL) suppressed the IFN gamma/IL-10 ratio. It is concluded that intracellular 5-HT may be necessary for an optimal synthesis of IFN gamma and IL-10, and that extracellular 5-HT concentrations at or above serum values may suppress the production of the proinflammatory cytokine IFN gamma. The negative immunoregulatory effects of antidepressive drugs are probably not related to their serotonergic activities. [Neuropsychopharmacology 23:89-98, 2000] (C) 2000 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. All rights reserved.