Tricyclic antidepressants inhibit IL-6, IL-1β and TNF-α release in human blood monocytes and IL-2 and interferon-γ in T cells

203

Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNFSeveral lines of evidence indicate that antidepressants produce various immunomodulatory effects. In depressed patients, the effects of antidepressants are variable and seem to be related to the immune status of the patients at the initiation of the treatment. When depression was associated with immune activation, antidepressants reduced immune function and cytokine secretion. For example, the increased plasma levels of IL-6 during acute depression were normalized by 8-week treatment with fluoxetine (Sluzewska et al. 1995), the increased monocyte counts in depressed patients were reduced following 6-weeks treatment with tricyclic antidepressants (TCAs) (Seidel et al. 1996), and the increased numbers of leukocytes and neutrophils were also reduced by antidepressant treatment (Maes et al. 24 , NO . 5 1997). On the other hand, when immune functions were found to be normal, antidepressants had no immunological effects; for example, chronic moclobemide treatment had no effect on monocytes functions, TNF ␣ production or IFN ␥ levels (Landmann et al. 1997). Moreover, in a study of depressed patients who exhibited immune suppression before treatment, the TCA clomipramine increased the production of IL-1 ␤ , IL-2, and IL-3 (Weizman et al. 1994).In experimental animals, TCAs as well as selective serotonin reuptake inhibitors (SSRIs) produce mainly immune suppression and anti-inflammatory effects. For example, antidepressant treatment in vivo inhibited the increased acute phase response in olfactory bulbectomized rats, a useful animal model of depression (Song and Leonard 1994), reduced the production of interleukin-1 (IL-1) and IL-2 in a chronic mild stress model of depression (Kubera et al. 1996), inhibited immune activation in rats with experimental allergic neuritis (Zhu et al. 1994), and produced anti-inflammatory ...

Section: Discussionmentioning

confidence: 71%

Section: Antidepressants Produce Various Immunomodulatory Effects Asmentioning

confidence: 98%

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Yirmiya

Pollak

Barak

et al. 2001

203

“…If increased production of pro-inflammatory cytokines is at all involved in the etiology of depression one would expect that antidepressive treatments have negative immunoregulatory effects. Recently, Xia et al (1996) showed clomipramine, imipramine, and citalopram significantly suppressed the secretion of IL-2 by stimulated T lymphocytes and of IL-1 ␤ and TNF ␣ by stimulated monocytes. Moreover, there was a trend toward a significant decreased secretion of IFN ␥ by stimulated T lymphocytes preincubated with the above antidepressants (Xia et al 1996).…”

mentioning

confidence: 99%

“…Recently, Xia et al (1996) showed clomipramine, imipramine, and citalopram significantly suppressed the secretion of IL-2 by stimulated T lymphocytes and of IL-1 ␤ and TNF ␣ by stimulated monocytes. Moreover, there was a trend toward a significant decreased secretion of IFN ␥ by stimulated T lymphocytes preincubated with the above antidepressants (Xia et al 1996). Recently, it has been shown that diluted whole blood stimulated with phytohemagglutinin (PHA) ϩ lipopolysaccharide (LPS) offers the most appropriate and reproducible culture condition in order to measure cytokines, such as IFN ␥ , IL-6, andIL-1 (review: De Groote et al 1992, 1993;Zangerle et al 1992).…”

mentioning

confidence: 99%

Negative Immunoregulatory Effects of Antidepressants Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

Maes¹,

Song

Lin

et al. 1999

339

179

“…Xia et al (1996) reported that TCAs as well as SSRIs significantly elevate intracellular cAMP concentrations in T lymphocytes and monocytes. Elevation of the intracellular levels of cAMP differently affects the production of IL-10 and IFN␥ (Benbernou et al 1997).…”

Section: Discussionmentioning

confidence: 99%

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

Kubera¹,

Kenis²,

Bosmans³

et al. 2000

(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...