Antidepressants suppress production of the Th₁ cytokine interferon-γ, independent of monoamine transporter blockade

Abstract

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-1β, TNF-α, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th₁: IFN-γ and Th_2 / 3: IL-10) cytokines. All of the antidepressants suppressed IFN-γ production in the 10–50 μM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-γ production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-γ production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-γ 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 μM) 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-γ producing T-cells (Th₁ 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.

Introduction

One of the most intriguing theories concerning the aetiology of depressive illness suggests that an activated immune system resulting in excessive secretion of monocyte and/or T-cell-derived pro-inflammatory cytokines has the propensity to precipitate depression in susceptible individuals (see Capuron and Dantzer, 2003, Connor and Leonard, 1998, Maes et al., 1995, Smith, 1991, Yirmiya, 2000). In support of this theory, experimental studies clearly demonstrate that induction of pro-inflammatory cytokines using bacterial lipopolysaccharide, or exogenous administration of cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α and interferon (IFN)-α can induce alterations in behaviour, neurotransmitter function and neuroendocrine output similar to those observed in depressed patients (see Anisman and Merali, 2002, Capuron and Dantzer, 2003, Connor and Leonard, 1998, Dunn and Crnic, 1993). In addition, several clinical studies indicate that depressive illness is associated with activation of the inflammatory response system resulting in increased circulating concentrations of monocyte and T-cell-derived pro-inflammatory cytokines in depressed patients: IL-1β (Owen et al., 2001); IL-6 (Miller et al., 2002, Sluzewska et al., 1996); IL-12 (Kim et al., 2002); IL-18 (Kokai et al., 2002); TNF-α (Hestad et al., 2003) and IFN-γ (Maes et al., 1994). However, possibly the most compelling evidence indicating a role for cytokines in depressive illness stems from the fact that treatment of humans with low dose endotoxin, or recombinant cytokines such as IL-2 and IFN-α can induce depressive symptomatology (see Capuron and Dantzer, 2003, Reichenberg et al., 2001).

Due to the suggestion that increased production of pro-inflammatory cytokines may play a causal role in depressive illness, the ability of antidepressants to promote an anti-inflammatory cytokine phenotype is a subject of considerable interest (see Castanon et al., 2002, Connor and Leonard, 1998, Kenis and Maes, 2002, Nishida et al., 2002). However, despite evidence indicating that antidepressants have anti-inflammatory potential, little is known about the precise mechanism(s) underlying such effects. Whilst the majority of currently used antidepressants act as serotonin or noradrenaline reuptake inhibitors (see Nelson, 1999), the role of serotonin or noradrenaline reuptake blockade in antidepressant-induced immunomodulation has not been explored. In addition to their expression within the central nervous system, evidence indicates that serotonin and noradrenaline transporters are also expressed on peripheral blood mononuclear cells (Faraj et al., 1994, Marino et al., 1999, Urbina et al., 1999). Moreover serotonin and noradrenaline are released from lymphocytes and monocytes (Finocchiaro et al., 1988, Marino et al., 1999), and can elicit immunomodulatory properties via receptors present on immune cells (see Elenkov et al., 2000, Mossner and Lesch, 1998). Thus it is feasible that pharmacological blockade of monoamine transporters has the propensity to alter immune functioning by increasing the local concentrations of serotonin or noradrenaline in the vicinity of immune cells. However to date, the role of monoamine transporters in mediating the immunomodulatory effects of antidepressants has not been addressed.

Therefore in the present study, we examined the effect of first- and second-generation antidepressants, with selectivity for the serotonin transporter (fluoxetine and clomipramine) (see Leonard, 2003, Nelson, 1999) or the noradrenaline transporter (reboxetine and desipramine) (see Nelson, 1999, Wong et al., 2000) on monocyte and T-cell derived cytokine production. In addition, we also examined the ability of trimipramine; a tricyclic antidepressant that lacks significant monoamine reuptake inhibitory properties on cytokine production (Gastpar, 1989, Richelson and Pfenning, 1984). To our knowledge, this is the first study to systematically compare the actions of first- and second-generation antidepressants with differential effects on noradrenaline and serotonin transporters on T-cell and monocyte-derived cytokine production at a range of dose levels. Overall, the data generated in this study indicate that IFN-γ producing T-cells (Th₁ cells) are the major target of the immunomodulatory actions of antidepressants, and also provide evidence that questions the relationship between the monoaminergic reuptake properties of these compounds and their immunomodulatory properties.