Paroxetine differentially modulates LPS-induced TNFα and IL-6 production in mouse macrophages

Abstract

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is clinically used for the treatment of depression in human patients. Because of recent reports on the role of serotonin in modulating inflammation and the link between inflammation and depression, we sought to test the effect of paroxetine directly on macrophage response to an inflammatory stimulus. Lipopolysaccharide (LPS) treatment of mouse macrophages significantly enhanced TNFα and IL-6 production. Paroxetine treatment of macrophages however, significantly inhibited LPS-induced IL-6 production. In contrast, paroxetine enhanced LPS-induced TNFα production in macrophages. These effects of paroxetine were mimicked by fluoxetine, another SSRI. To determine if the effects of paroxetine are mediated via modulation of the 5-HT system, we treated macrophages with 5-HT or 5-HT receptor antagonist (LY215840) in the presence of LPS and/or paroxetine. 5-HT treatment by itself did not affect LPS-induced cytokine production. LY215840 however, reversed paroxetine's effect on LPS-induced TNFα production but not IL-6. To understand the signaling mechanisms, we examined paroxetine's effect on MAPK and NFκB pathways. While paroxetine inhibited LPS-induced IκBα phosphorylation, MAPK pathways were mostly unaffected. Together these data demonstrate that paroxetine has critical but differential effects on IL-6 and TNFα production in macrophages and that it likely regulates these cytokines via distinct mechanisms.

Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages

“…We found no evidence that either of the monoaminergic antidepressant drugs tested (TCA or SSRI) exerted any effect on the response in MDMs to LPS or IFNα. This is in contrast to reports that TCAs reduce proinflammatory signaling in phagocytes,68 and SSRIs have been reported to alter macrophage differentiation and inflammatory signaling 67, 69. SSRIs have also been reported to modulate glucocorticoid actions on monocytes 70.…”

“…This is in contrast to reports that TCAs reduce proinflammatory signaling in phagocytes, 68 and SSRIs have been reported to alter macrophage differentiation and inflammatory signaling. 67,69 SSRIs have also been reported to modulate glucocorticoid actions on monocytes. 70 Although we found no direct effect of SSRIs or TCAs on macrophage responses to either LPS or IFN , we did observe significant cytotoxicity at concentrations that were <20-fold lower than circulating blood concentrations in treated patients.…”

<p>Mitigation of Rheumatic Arthritis in a Rat Model via Transdermal Delivery of Dapoxetine HCl Amalgamated as a Nanoplatform: In vitro and in vivo Assessment</p>

“…Many studies have shown the anti-inflammatory effects of SSRIs. For example, Durairaj et al 98 showed that the SSRI paroxetine has critical but differential effects on IL-6 and TNF-α production in macrophages, which likely involves distinct mechanisms. Furthermore, Fonseka et al 99 reported that an SSRI can modulate the elevated IL-6-levels associated with major depressive disorder.…”

Paroxetine modulates immune responses by activating a JAK2/STAT3 signaling pathway

“…[ 11 ] More importantly, media containing fetal bovine serum (FBS) has indicated to have high concentrations of serotonin. [ 12 ] Serotonin (5‐HT) can modulate the production of a number of inflammatory cytokines, including IL‐2, IL‐16, IFN‐γ, IL‐1β, TNF‐α, and IL‐6. [ 11 ] Moreover, studies suggested that proinflammatory cytokines increase serotonin reuptake via SERT activity enhancement so neglecting serotonin and SSRIs' mutual interrelations seems inconceivable.…”