Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

Abstract

Inappropriate functioning of the immune system is observed during sustained systemic inflammation, which might lead to immune deficiencies, autoimmune disorders and cancer. Primary lymphoid organs may progress to a deregulated proliferative state in response to inflammatory signals in order to intensify host defense mechanisms and exacerbate an inflammatory niche. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been projected as an anti‐inflammatory agent. This study had been designed to evaluate the potential novel role of fluoxetine in reversing inflammation‐induced immune dysfunction. Lipopolysaccharide (LPS) administration in Swiss albino mice potentiated a systemic inflammatory response, along with increased proliferation of thymocytes and peripheral blood mononuclear cells, as evident from increased Ki‐67 expression. The proliferative changes in the immune system were mainly associated with increased phosphorylation of PI3k, AKT and IκB along with elevated NFκB‐p65 nuclear translocation. The Ki‐67high thymocytes obtained from LPS administered mice demonstrated significantly low p53 nuclear activity, which was established to be mediated by NFκB through reduced nuclear translocation of p53 during LPS‐induced proliferative conditions, thereby blocking p53‐dependent apoptosis. Fluoxetine supplementation not only reversed the proinflammatory condition, but also induced selective apoptosis in the proliferation‐dictated Ki‐67high thymocytes possibly by modulating the hypothalamus–pituitary–adrenal axis and inducing glucocorticoid receptor activation and apoptosis in these proliferation‐biased immune cells, authenticating a novel antiproliferative role of an established drug.