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doi:10.1016/j.intimp.2004.11.008 
Copyright © 2004 Elsevier B.V. All rights reserved.
The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway
Michael Maesa, b, c, Gunter Kenisa, Marta Kuberad, 
, 
, Mark De Baetse, Harry Steinbusche and Eugene Bosmansa
Received 10 November 2004;
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Abstract
Recently, we have shown that various types of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, have negative immunoregulatory effects. These antidepressants suppress the interferon-γ (IFN-γ)/interleukin-10 (IL-10) production ratio, which is of critical importance for the determination of the capacity of immunocytes to inhibit or activate monocytic/lymphocytic functions. Since cyclic adenosine monophosphate (cAMP) production is stimulated by some antidepressants, and since cAMP inhibits IFN-γ and stimulates IL-10 production, we postulate that the negative immunoregulatory effects of antidepressants result from their effects on the cAMP-dependent protein kinase A (PKA) pathway. The aim of the present study was to determine whether the negative immunoregulatory effects of fluoxetine may be blocked by antagonists of the cAMP-dependent PKA pathway, such as, e.g., SQ 22536, an adenylate cyclase inhibitor, and Rp-8-Br-cAMPs (Rp-isomer of 8-bromo-adenosine-3′,5′-monophosphorothioate), a PKA antagonist. To this end, diluted whole blood collected from 17 normal volunteers was incubated with fluoxetine (10−6 and 10−5 M), with or without SQ 22536 (10−6 and 10−4 M) and Rp-8-Br-cAMPs (10−6 and 10−4 M), afterwards, IFN-γ, IL-10 and the tumor necrosis factor α (TNF-α) were determined. Fluoxetine, 10−6 and 10−5 M, significantly reduced the production of IFN-γ and TNF-α, and significantly decreased the IFN-γ/IL-10 production ratio. SQ 22536 and Rp-8-Br-cAMPs were unable to block the suppressant effects of fluoxetine on the IFN-γ/IL-10 ratio. Rp-8-Br-cAMPs, 10−4, but not 10−6 M, normalized the fluoxetine-induced suppression of TNF-α production. It is concluded that the suppressant effect of fluoxetine on the IFN-γ/IL-10 production ratio is probably not related to the induction of the cAMP-dependent PKA pathway, whereas the suppressant effect on TNF-α may be related to the induction of PKA. The obtained results suggest that increased activation of the PKA-dependent pathway may constitute an important molecular basis for some (suppression of TNF-α production), but not all (suppression of IFN-γ production), negative immunoregulatory effects of fluoxetine.
Keywords: Antidepressants; Depression; Cytokines; cAMP; PKA; Second messengers; Fluoxetine
