Immunostimulatory and immunomodulatory effects of duloxetine and venlafaxine on p38 MAPK and PI3K pathways

Anti-depressants have been used more widely throughout the world. Their mood altering activities are appreciated but determining their side effects or possible effects on the immune system is crucial. In our study, we focused on two prominent drugs that have been used against anxiety and depression. Serotonin and norepinephrine reuptake inhibitor (SNRI) anti-depressants Duloxetine and Venlafaxine were tested in vitro on the mammalian macrophages. Their immunostimulatory (inflammatory potential) activities were tested on inactivated macrophages whereas their immunomodulatory, possible anti-inflammatory activities were tested on the LPS activated macrophages. The production levels of pro-inflammatory cytokines were measured by ELISA. The levels of phosphorylated (active) p38 MAPK and PI3K proteins were determined by flow cytometry analysis and their possible intracellular mechanisms of action were demonstrated. According to our results, these drugs had differential effects on the macrophages. Duloxetine triggered a mild inflammatory response in the unactivated macrophages whereas; it had anti-inflammatory effects on already activated macrophages. Venlafaxine lacked this immunostimulatory activity on unactivated macrophages and had mild anti-inflammatory activities on the activated macrophages. These results suggest that these drugs can be differentially utilized against patients with inflammatory problems (Duloxetine) and patients without inflammatory problems (Venlafaxine).