Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade.
In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-gamma production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-gamma production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and desipramine. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-gamma producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-N CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-Y GENE-N CHEMICAL GENE-Y GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
tricyclic monoamine noradrenaline serotonin reboxetine noradrenaline desipramine monoamine IFN-gamma IFN-gamma trimipramine serotonin transporter IL-10 cytokine cytokine IFN-gamma cytokine cytokine IL-1beta TNF-alpha IL-12 serotonin noradrenaline transporter IL-10 cytokines IFN-gamma IL-10 cytokines IFN-gamma serotonin or noradrenaline transporters IFN-gamma cytokine monoamine interferon-gamma monoamine transporter fluoxetine noradrenaline reboxetine desipramine clomipramine trimipramine