Tricyclic antidepressants inhibit human natural killer cells

The commonly used antidepressants imipramine, amitriptyline, and nortriptyline were found to significantly inhibit human natural killer (NK) cell-mediated cytolysis in vitro and suppress the stimulation of NK cells by IFN-gamma. This is a previously unrecognized biologic property of these drugs with psychotropic activity. Tricyclic antidepressants did not decrease effector-target cell conjugation formation, nor did they induce target cell resistance to NK lysis, indicating that the drugs might interfere with the killing mechanism of the effector cells. Kinetic data reveal that the drug interference is related to an early postbinding event in the activation of NK cells. Results also showed that the inhibitory effect of tricyclic antidepressants on human NK cell activity occurred in parallel to an increase in intracellular cyclic GMP concentration. However, the attenuation in the cyclic GMP formation by methylene blue, a selective inhibitor of soluble guanylate cyclase, was not accompanied by a corresponding increase in NK cell cytolytic activity. It is suggested that the stimulation of cyclic GMP was not directly involved in the inhibitory effect of antidepressants on NK cells and perhaps was a secondary phenomenon. This immune cell modulatory property of tricyclic antidepressants seems to indirectly provide evidence for the concept that human brain neurons and NK cells might share regulatory system(s).