In vitro studies on the potential immunosuppressive and antitumor effects of antidepressants : induction of apoptosis in human T-cells and a myeloid leukemia cell line

Sammanfattning: Antidepressants are widely used in treating depressive disorders. It has been demonstrated that several components of the immune system may be activated in the acute clinical stage of major depression and that such activation may play a role in the onset of depressive symptoms. This suggested involvement of activation of the immune system in depression gives rise to the hypothesis that antidepressants have an inhibitory effect on the immune system.Therefore, we were interested in investigating possible molecular effects of antidepressants on cells involved in immunological defenses. We found that incubation of human peripheral T-cells with the antidepressants imipramine, clomipramine and citalopram in vitro inhibits phytohaemagglutinin-induced interlukin-2 (IL-2) and interferon-g(IFN-g) release. The secretion of interlukin-1b(IL-1b), tumor necrosis factor-a(TNF-a) and interlukin-6 (IL-6) by peripheral monocytes caused by lipopolysaccharide is also inhibited by these compounds.Our further investigations demonstrated that these drugs induce apoptotic cell death in human peripheral T-cells in vitro , which may account for their immunosuppressive effects. This apoptosis was shown to be dose- and time-dependent and could be abolished by exogenous IL-2 (a pro-inflammatory cytokine), reduced glutathione (an antioxidant) and aurintricarboxylic acid (a nuclease inhibitor). This process could not be inhibited by the translation inhibitor cycloheximide or the transcription inhibitor actinomycin D, indicating that protein and RNA synthesis are not required.Furthermore, we have shown that these drugs also induce apoptosis in human acute myeloid leukemia HL-60 cells, which might explain the antineoplastic effects known to be exerted by these compounds. Antidepressant-induced apoptosis in HL-60 cells is associated with an early increase in the production of reactive oxygen species (ROS), subsequent loss of mitochondial membrane potential (Dym) and activation of a caspase-3-like protease(s). Early hypergeneration of ROS may thus be an initial signal in antidepressant-induced apoptosis. Overexpression of the antiapoptotic protein Bcl-2 or Bcl-XL prevents drug-induced apoptosis, as well as loss of Dym, but does not affect the generation of ROS.