RESUMO
Recently, we developed a nonhemodynamic dopamine derivative, NOD, which has profound anti-inflammatory effects in vitro. As NOD also protects rats from ischemic AKI, the present study tested whether NOD is able to modulate cellular immunity for potential use as a T cell-suppressive agent. To this end, T cells were stimulated by anti-CD3/CD28 or PMA/ionomycin in the presence or absence of different concentrations of NOD. T cell proliferation, activation markers, intracellular cytokine expression, and activation of transcription factors were assessed. Whereas T cell proliferation was inhibited significantly by NOD at Day 3, proliferation was restored at Day 7 or later depending on the NOD concentration used. Inhibition of proliferation was reflected by a diminished CD25 expression and switch from naive to memory T cells. Early TCR activation events were unaffected, yet NF-κB and AP-1 were strongly inhibited by NOD. The inhibitory effect of NOD seemed to be dependent on its redox activity, as NOT, a redox-inactive NOD derivate, did not influence proliferation. NOD displayed synergistic effects with CNIs on T cell proliferation. Our data demonstrate that NOD displays T cell-suppressive activity. In keeping with its anti-inflammatory action and its beneficial effect on ischemia-induced AKI, NOD may be an interesting drug candidate to prevent CNI-related side-effects.
Assuntos
Dopamina/análogos & derivados , Fase G1/efeitos dos fármacos , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Inibidores de Calcineurina/farmacologia , Divisão Celular/efeitos dos fármacos , Dopamina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Memória Imunológica , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Oxirredução , Estresse Oxidativo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Complexo Receptor-CD3 de Antígeno de Linfócitos T/efeitos dos fármacos , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Linfócitos T/citologia , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/metabolismo , Proteína-Tirosina Quinase ZAP-70/metabolismoRESUMO
We have studied the effects of the marine algal toxins yessotoxin (YTX) and okadaic acid (OA) on the T cell receptor complex (TCR) expression, an important mechanism by which T cell responsiveness is controlled. Immune system cells are relevant targets to study the immunoregulatory potential of marine toxins since the immune system has been reported as one of the targets of marine algal toxins. This study reports results from exposing the mouse T lymphocyte cell line EL-4 to increasing concentrations of YTX and OA for 72h. We found that both YTX and OA affected TCR recycling kinetics and induced a specific and reversible TCR down-regulation in T lymphocyte EL-4 cells that was time and concentration dependent. Experiments using the potent protein kinase C (PKC) inhibitor stausporine indicated that YTX-induced TCR down-regulation was partially mediated by PKC activation. In contrast, OA-induced TCR down-regulation was mediated by the serine/threonine protein phophatase 2A (PP2A) inhibition. In summary, the results suggest that OA and YTX concentrations in a similar range than those detected in mice bloodstream after oral administration have the potential to adjust the T cell responsiveness during the initiation of T cell activation by affecting the TCR expression levels via PKC and PP2A activities.