Paroxetine differentially modulates LPS-induced TNFα and IL-6 production in mouse macrophages.
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.
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Haritha
H
Durairaj
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Michael D
MD
Steury
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: paramesw@msu.edu.
Narayanan
N
Parameswaran
D000818:Animals; D002460:Cell Line; D005473:Fluoxetine / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides; D008237:Lysergic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017374:Paroxetine / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D005473:Fluoxetine; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008237:Lysergic Acid; D017374:Paroxetine; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; C074025:LY 215840
Cytokines; Macrophage; Paroxetine; SSRI; Serotonin; TLR4