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Fluoxetine triggers selective apoptosis in inflammation-induced proliferating (Ki-67high) thymocytes
S GHOSH, S CHOUDHURY, S MUKHERJEE, P GUPTA, O CHOWDHURY, R BARAL,
Published in John Wiley and Sons Inc.
2019
PMID: 30582666
Volume: 97
   
Issue: 5
Pages: 470 - 484
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. © 2018 Australasian Society for Immunology Inc.
About the journal
JournalData powered by TypesetImmunology and Cell Biology
PublisherData powered by TypesetJohn Wiley and Sons Inc.
ISSN0818-9641
Open AccessNo