RESUMO
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.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Glucocorticoides/farmacologia , Pregnadienos/farmacologia , Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Dexametasona/farmacologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
We investigated the energy-adaptive potential of human CD4(+) T cells under conditions of impaired oxidative phosphorylation (OXPHOS) and/or low glucose (inhibiting glycolysis). These cells often encounter these conditions when executing their functions in injured/inflamed tissues, even though T cells themselves require constant and adequate energy supply via ATP. We assessed two specific functions, cytokine synthesis and proliferation, and addressed whether adaptive characteristics also emerged in vivo. In glucose-containing medium, both cytokine production and proliferation were unaffected, even under complete OXPHOS suppression. Only when glucose was also absent were these functions significantly decreased. Partial recovery of OXPHOS and induced glycolysis were crucial for the maintenance of cellular energy supply. Adaptive regulatory mechanisms are clinically relevant because hypoxia up-regulates glycolytic genes but down-regulates OXPHOS genes in vivo. Our data demonstrate an unexpectedly high, clinically relevant adaptive potential of human CD4(+) T cells to maintain specific functions even under severely impaired bioenergetic conditions.