The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway.
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-gamma (IFN-gamma)/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-gamma 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-gamma, IL-10 and the tumor necrosis factor alpha (TNF-alpha) were determined. Fluoxetine, 10(-6) and 10(-5) M, significantly reduced the production of IFN-gamma and TNF-alpha, and significantly decreased the IFN-gamma/IL-10 production ratio. SQ 22536 and Rp-8-Br-cAMPs were unable to block the suppressant effects of fluoxetine on the IFN-gamma/IL-10 ratio. Rp-8-Br-cAMPs, 10(-4), but not 10(-6) M, normalized the fluoxetine-induced suppression of TNF-alpha production. It is concluded that the suppressant effect of fluoxetine on the IFN-gamma/IL-10 production ratio is probably not related to the induction of the cAMP-dependent PKA pathway, whereas the suppressant effect on TNF-alpha 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-alpha production), but not all (suppression of IFN-gamma production), negative immunoregulatory effects of fluoxetine.
Maes
Michael
M
Department of Psychiatry, University Hospital of Maastricht, Vijverdal P.O. Box 88, 6200 AB Maastricht, The Netherlands.
Kenis
Gunter
G
Kubera
Marta
M
De Baets
Mark
M
Steinbusch
Harry
H
Bosmans
Eugene
E
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000242:Cyclic AMP / Q000502:physiology*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; C433788:lipopolysaccharide, E. coli O26-B6; D005473:Fluoxetine; D016753:Interleukin-10; C017759:9-(tetrahydro-2-furyl)-adenine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D007371:Interferon-gamma; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D000225:Adenine