title: The 5-HT3 receptor antagonist tropisetron inhibits T cell activation by targeting the calcineurin pathway.
abstract: Tropisetron, an antagonist of serotonin type 3 receptor, has been investigated in chronic inflammatory joint process. Since T cells play a key role in the onset of several inflammatory diseases, we have evaluated the immunosuppressive activity of tropisetron in human T cells, discovering that this compound is a potent inhibitor of early and late events in TCR-mediated T cell activation. Moreover, we found that tropisetron specifically inhibited both IL-2 gene transcription and IL-2 synthesis in stimulated T cells. To further characterize the inhibitory mechanisms of tropisetron at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-(kappa)B, NFAT and AP-1 transcription factors in Jurkat T cells. We found that tropisetron inhibited both the binding to DNA and the transcriptional activity of NFAT and AP-1. We also observed that tropisetron is a potent inhibitor of PMA plus ionomycin-induced NF-(kappa)B activation but in contrast TNF(alpha)-mediated NF-(kappa)B activation was not affected by this antagonist. Finally, overexpression of a constitutively active form of calcineurin indicated that this phosphatase may represent one of the main targets for the inhibitory activity of tropisetron. These findings provide new mechanistic insights into the anti-inflammatory activities of tropisetron, which are probably independent of serotonin receptor signalling and highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.
authors.affiliation: Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Avda Menendez Pidal, s/n, 14004 Córdoba, Spain.
authors.forename: Laureano de la
authors.initials: Lde L
authors.lastname: Vega
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.forename: Klaus
authors.initials: K
authors.lastname: Lieb
authors.forename: Eduardo
authors.initials: E
authors.lastname: Candelario-Jalil
authors.forename: Harald
authors.initials: H
authors.lastname: Gschaidmeir
authors.forename: Lothar
authors.initials: L
authors.lastname: Färber
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller
authors.forename: Thomas
authors.initials: T
authors.lastname: Stratz
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Fiebich
mesh_terms: D019703:Calcineurin / Q000502:physiology*; D002999:Clone Cells; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D000077526:Tropisetron
chemical_list: D007166:Immunosuppressive Agents; D007211:Indoles; D007376:Interleukin-2; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D000077526:Tropisetron; D019703:Calcineurin