Effects of Serotonin and Serotonergic Agonists and Antagonists on the Production of Interferon-γ and Interleukin-10

Abstract

(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 be 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 , and ritanserin (a 5-HT2A/ 2C antagonist) on the production rate of interferon-␥ (IFN ␥ ), a proinflammatory cytokine, and IL-10 by whole blood stimulated with polyclonal activators. The IFN ␥ /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 g/ mL, and 15 g/mL significantly decreased the IFN ␥ /IL-10 ratio; 2) PCPA (5 M) significantly suppressed the production of 3) Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter, a vasoactive amine released by platelets at sites of inflammation and an immune modulator (Roszman et al. 1985;Mossner and Lesch 1998;Kubera and Maes 1999). In humans, 5-HT is produced, outside the central nervous system, by enterochromaffin cells and it is stored in circulating platelets and to a lesser extent in monocytes and lymphocytes (Essmann 1978). 5-HT is released from platelets and lymphocytes/monocytes following stimulation by platelet activating factors or lectins/interferon-␥ (IFN ␥ ), respectively (Finocchiaro et al. 1988 (Cohen et al. 1985;Felten et al. 1991). Pharmacological and molecular analyses have confirmed the presence of 5HT1A and 5HT2A/C receptors on activated human immunocytes and specific 5-HT transporter sites on macrophages/ lymphocytes (Aune et al. 1994).The effect of 5-HT on cell-mediated immunity and on the inflammatory response system (IRS) is still a matter of controversy. Some studies show that 5-HT has immunosuppressive effects. Devoino et al. (1968) reported that substances, which have the property to increase 5-HT concentrations, inhibit immunogenesis and antibody production in rodents. 5-HT may suppress delayed hypersensitivity and transplantation immunity (for review see Devoino and Morozova 1988). Bonnet et al. (1984) found that 5-HT suppresses murine lymphocytic response to phytohemagglutinin A (PHA) and/or allogeneic cells. p-Chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, enhances the production of antibodies . Other immune functions, however, may be stimulated by 5-HT. For example, cutaneous injection of 5-HT can initiate a delayed-type hypersensitivity reaction through local recruitment and activation of CD4 ϩ T-helper cells (Ptak et al. 1991). Low doses (100 ng/ml) of exogenously added 5-HT stimulate T cell proliferation in response to interleukin-2 (IL-2) (Young et al. 1993; Young and Mathews 1995). Enhancement of murine T-cell blastogenesis by 5-HT has b...

Depression has a Strong Relationship to Alterations in the Immune, Endocrine and Neural System

“…Other routes than IDO / TDO proinflammatory cytokines may also be involved in changes in NA and 5-HT. Inflammatory cytokines may directly affect 5-HT turnover (reuptake and degradation) as well as receptor distribution and sensitivity in brain regions presumed to be involved in depression such as hypothalamus, hippocampus, amygdala and prefrontal cortex [123,[145][146][147][148][149], reinforcing the IDO / TDO mediated effect on serotonin.…”

Specific Serotonin Reuptake Inhibitor-Induced Decreases in Lymphocyte Activity Require Endogenous Serotonin Release

“…Although our laboratory has previously shown that fluoxetine will decrease splenic lymphocyte proliferation in vitro at higher doses [34], it is not likely that the effects of fluoxetine observed in vivo are due to direct effects of fluoxetine on immune cells, since suppression is observed only in animals with an intact serotonergic system. However, fluoxetine might be acting in the periphery to modulate immune cell function through elevations in plasma or local serotonin levels, since serotonin has been shown to decrease immune cell function at higher concentrations, when applied to immune cells in vitro [45,[64][65][66]. Another possibility is that elevations in central serotonin levels following fluoxetine resulted in activation of CNS modulatory systems.…”

“…These drugs bind to other receptors that could interfere with proliferative responses, such as H 1C histamine receptors [36] and ion channels, including potassium, calcium and sodium [37][38][39][40][41][42][43][44]. One example, the SSRI, sertraline, has been shown to decrease the IFNÁ/IL-10 ratio by increasing IL-10 secretion [35], whereas 5-HT also decreases the IFNÁ/IL-10 ratio but it does so by decreasing IFNÁ rather than increasing IL-10 secretion [45]. Therefore, it appears that the effects of sertraline on production of these cytokines are not related to its serotonergic activity.…”

2-Aminotetraline Derivative Protects from Ischemia/Reperfusion Brain Injury with a Broad Therapeutic Window

“…Although thus far the localization of these 5-HT receptor subtypes in the brain is largely unknown and further studies are ongoing to better 2-Aminotetraline in ischemic injury C Capone et al define their specific function (Leysen, 2004), these data indicate that they may be involved in the control of inflammatory molecule release. Actually serotonin is known to be involved in a wide spectrum of immune response modulatory activity (Hellstrand et al, 1993;Kubera et al, 2000Kubera et al, , 2005Young and Matthews, 1995). Interestingly, one recent study proposes a specific involvement of 5-HT2B receptors in the regulation of inflammatory cytokine production from blood cells (Kubera et al, 2005), and a second one shows that stimulation of 5-HT2B receptors leads to a TNF-a converting enzyme-dependent TNF-a release, thus linking activation of these receptors to an increased expression of pro-inflammatory cytokines (Pietri et al, 2005).…”