The Inhibitory Effects of Fluoxetine on Secretion of Inflammatory Mediators and Genes Expression of JAK/STAT3 and JNK/TLR4

Abstract

Abstract Background Selective serotonin reuptake inhibitors (SSRIs) as the commonest therapeutic option are used to treat major depression. Recent studies have reported an association between depression and inflammation as well as the significant effect of SSRIs on inflammatory processes. Methods The current research was done to evaluate the impact of fluoxetine as a SSRI on the level of key inflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), in rat serum and RAW264.7 macrophages using ELISA sandwich assays. We also assessed the expression of inflammatory genes, JAK/STAT3 and TLR4/ JNK, in macrophages using quantitative real-time RT-PCR to elucidate the potential mechanism of fluoxetine on inflammation process. Rats received fluoxetine (10, 20, 40 mg/kg), 30 minutes before treatment with lipopolysaccharide (LPS) for 90 minutes and cells received different doses (5, 10, 20 µg/ml) of fluoxetine prior to 24 or 48 h stimulation with LPS. Results The serum concentrations of IL-1β, IL-6 and TNF-α reduced in rats and cells pre-treated with fluoxetine. The expression of JAK/STAT3 and TLR4/ JNK genes was significantly decreased by fluoxetine in RAW264.7 cells treated for 24 h with LPS. However, fluoxetine failed to reduce the elevated expression of JAK and JNK but significantly decreased the gene expression of STAT3 and TLR4 after 48 h treatment with LPS. Conclusions Our data demonstrates that fluoxetine has anti-inflammatory properties, mainly due to reduction of inflammatory cytokines and the inhibition of JAK/STAT3 and TLR4/ JNK genes expression in macrophages.