RESUMO
Accumulating evidence has shown that mammalian target of rapamycin (mTOR) pathway and myeloid-derived suppressor cells (MDSCs) are involved in pathogenesis of inflammatory bowel diseases (IBDs). INK128 is a novel mTOR kinase inhibitor in clinical development. However, the exact roles of MDSCs and INK128 in IBD are unclear. Here, we showed that the INK128 treatment enhanced the resistance of mice to dextran sodium sulfate (DSS)-induced colitis and inhibited the differentiation of MDSCs into macrophages. Moreover, interferon (IFN)-α level was elevated in INK128-treated colitis mice. When stimulated with IFN-α in vitro, MDSCs showed a superior immunosuppression activity. Of note, the regulatory T cells (Tregs) increased but Th1 cells decreased in INK128-treated colitis mice. These results indicate that mTOR inhibitor INK128 attenuates DSS-induced colitis via Treg expansion promoted by MDSCs. Our work provides a new evidence that INK128 is potential to be a therapeutic drug on DSS-induced colitis via regulating MDSCs as well as maintaining Treg expansion.
Assuntos
Benzoxazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Colite/prevenção & controle , Colo/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Comunicação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/enzimologia , Colite/imunologia , Colo/enzimologia , Colo/imunologia , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/enzimologia , Células Supressoras Mieloides/imunologia , Células RAW 264.7 , Transdução de Sinais , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismoRESUMO
Since their 're-discovery' more than two decades ago, FOXP3+ regulatory T cells (Tregs) have been an important subject of investigation in the biomedical field and our understanding of the mechanisms that drive their phenotype and function in health and disease has advanced tremendously. During the past few years it has become clear that Tregs are not a terminally differentiated population but show some degree of plasticity, and can, under specific environmental conditions, acquire the phenotype of effector T cells. In particular, recent works have highlighted the acquisition of a Th1-like phenotype by Tregs in several pathological environments. In this review we give an update on the concept of Treg plasticity and the advances in defining the molecular mechanisms that underlie the generation of Th1-like Tregs during an immune response and in different disease settings.