Immunostimulatory activity of fluoxetine in macrophages via regulation of the PI3K and P38 signaling pathways

Abstract

Fluoxetine is an antidepressant drug that is heavily preferred in the cure of depression, which is from the selective serotonin reuptake inhibitor (SSRI) group. There are many reports on the effect of fluoxetine on the immune system, and its effect on the macrophage cells has never been looked at before. We aimed to demonstrate the cytokine production potential of fluoxetine antidepressant, which is widely used in the clinic, in the J774.2 cell line and its effect on PI3K and P38 pathways. The use of fluoxetine alone in J774.2 macrophage cells showed immunostimulatory properties by inducing the production of tumor necrosis factor-α (TNF-α), interleukin (IL) IL-6, IL-12p40, and granulocyte–macrophage colony-stimulating factor (GM-CSF) cytokines. It showed anti-inflammatory properties by completely stopping the production of cytokines (IL-6, IL12p40, TNF-α, and GM-CSF) at all concentrations where LPS and fluoxetine were used together. While PI3K and P38 pathways were not effective in the immunostimulatory effect in the presence of the drug agent, we found that the PI3K and P38 pathways were influenced during their anti-inflammatory activity.

Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

“…Thus, our data indicated that, at Dysregulation of cutaneous PI3K signalling may lead to severe pathological conditions characterized by uncontrolled cutaneous proliferation and inflammation, 59,86 and FX was already shown to interfere with this pathway. [38][39][40][41] Thus, our findings argued that, at least when applied at 14 μM, FX may exert its beneficial actions by directly or indirectly inhibiting the PI3K pathway. In order to challenge this hypothesis, we repeated our experiments by using the aforementioned PI3K inhibitor (GDC0941; 370 nM).…”

“…~0.4–2 μM) 76,77 found in FX‐treated patients. This, together with the aforementioned reports, 34,36–41 argued that the effects of FX may be mediated via the modulation of unexpected cellular targets. Having excluded three potential anti‐inflammatory mechanisms (i.e.…”

“…Although the idea that (at certain concentrations) FX is capable of influencing the activity of the PI3K is not unprecedented in the literature (see e.g. references 38–41 ), to the best of our knowledge, it is still unknown whether this is exerted via direct or indirect (or maybe combined, i.e. direct and indirect) inhibition of PI3K.…”

“…[33][34][35] Importantly, certain pieces of evidence argue that the antiinflammatory effects of FX might be independent of classical serotoninergic signalling, 34 and may rather be coupled to interactions with other pathways, including NLRP3-mediated inflammasome activation, 36 nitric oxide production, 37 or the phosphoinositide 3-kinase (PI3K) pathway. [38][39][40][41] Considering the remarkable safety profile of FX 42,43 as well as the aforementioned growing body of evidence supporting its additional beneficial biological effects, it is not surprising that repositioning it to treat various diseases and pathological conditions has already been suggested. 30,31,44,45 Thus, in the current study, we aimed to further explore its putative beneficial effects on human epidermal keratinocytes.…”

“…Moreover, recent studies demonstrated that, most likely due to direct antiviral and immune regulatory effects, FX administration beneficially influenced the clinical outcome in SARS‐CoV‐2 infection as well 33–35 . Importantly, certain pieces of evidence argue that the anti‐inflammatory effects of FX might be independent of classical serotoninergic signalling, 34 and may rather be coupled to interactions with other pathways, including NLRP3‐mediated inflammasome activation, 36 nitric oxide production, 37 or the phosphoinositide 3‐kinase (PI3K) pathway 38–41 …”