title: Rimexolone inhibits proliferation, cytokine expression and signal transduction of human CD4+ T-cells.
abstract: Rimexolone is a lipophilic glucocorticoid drug used for local application. Only few data are available describing its effects on immune cell functions. In this study we investigated the effects of rimexolone on the proliferation of human CD4+ T-cells using dexamethasone as standard reference. Isolated CD4+ T-cells were pre-incubated with rimexolone or dexamethasone at different concentrations for 10 min (10(-11)/10(-8)/10(-5)M) and stimulated with anti-CD3/anti-CD28 for 96 h. Proliferation was determined by flow cytometry. The percentage of dividing cells was significantly reduced by 10(-5)M rimexolone and dexamethasone; however, the average number of cell divisions was unchanged. In addition, production of IL-2 and other cytokines was reduced by both glucocorticoids at 10(-5)M. Interestingly, we observed a rimexolone-induced down-regulation of CD4 expression in unstimulated and non-dividing cells. The inhibitory effects on proliferation and CD4 expression could be blocked by the glucocorticoid-antagonist RU486 and were not due to glucocorticoid-induced apoptosis. Rimexolone and dexamethasone showed a similar potential to induce IkappaBalpha gene expression. We demonstrate rimexolone and dexamethasone to impair T-cell signalling pathways by rapid non-genomic suppression of the phosphorylation of Akt, p38 and ERK. We conclude that rimexolone and dexamethasone inhibit T-cell proliferation as well as cytokine production of activated CD4+ T-cells in a similar manner. As these inhibitory effects predominantly occur at high concentrations, a relatively high occupation-rate of cytosolic glucocorticoid receptors is needed, but receptor-mediated non-genomic effects may also be involved. It is implied that these effects contribute to the well-known beneficial anti-inflammatory and immunomodulatory effects of glucocorticoid therapy.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité University Hospital, Campus Mitte, Charitéplatz 1, Berlin, Germany. cornelia.spies@charite.de
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Spies
authors.forename: Timo
authors.initials: T
authors.lastname: Gaber
authors.forename: Martin
authors.initials: M
authors.lastname: Hahne
authors.forename: Lydia
authors.initials: L
authors.lastname: Naumann
authors.forename: Robert
authors.initials: R
authors.lastname: Tripmacher
authors.forename: Saskia
authors.initials: S
authors.lastname: Schellmann
authors.forename: Cindy
authors.initials: C
authors.lastname: Stahn
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D011245:Pregnadienes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D005938:Glucocorticoids; D011245:Pregnadienes; D003907:Dexamethasone; C013769:rimexolone