RESUMEN
All-trans retinoic acid (ATRA) affects on the function of antigen presenting cells with somewhat controversies. We investigated the effects of ATRA on differentiation, maturation and function of human monocyte-derived dendritic cells (DCs). Low dose (10(-14)M) or high dose (10(-6)M) of ATRA was added either when monocytes were differentiated into immature DCs (imDCs) or mature DCs (mDCs) were induced. Apoptotic cell populations were dramatically increased in imDCs or mDCs with increasing concentration of ATRA. The productions of IL-12p40 and IL-12p70 were significantly suppressed in imDCs or mDCs induced by the addition of ATRA in the dose-dependent manner, whereas IL-10 was increased. DCs cultured with ATRA induced the differentiation of naïve T cells towards a helper T cell type 2 (Th2) response and expansion of CD4(+)CD25(+)Foxp3(+) regulatory T cells. Allostimulatory capacity of DCs was suppressed with increasing concentration of ATRA. These findings suggest that ATRA inhibits the effects on the differentiation, maturation and function of human monocyte-derived DCs in vitro and also enhance the differentiation of naïve T cell toward the Th2 type.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Células Dendríticas/fisiología , Monocitos/efectos de los fármacos , Tretinoina/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/fisiología , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Dendríticas/metabolismo , Evaluación Preclínica de Medicamentos , Factores de Transcripción Forkhead/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Lectinas Tipo C/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Activación de Linfocitos/fisiología , Receptor de Manosa , Lectinas de Unión a Manosa/metabolismo , Monocitos/fisiología , Fenotipo , Receptores de Superficie Celular/metabolismo , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/fisiologíaRESUMEN
This study is performed to detect changes of gene expression in substantia nigra (SN) and striatum in manganese (Mn)-exposed mice brain. The cDNA array is a recently developed molecular biological method that can detect the differential expression of several hundreds of genes simultaneously and is therefore advantageous in the study of trace metal intoxication effect at the genetic level. Using this technology, we discovered 5 genes in the mouse striatum and 9 genes in SN changed by more than 50% following Mn exposure. Depression were observed in two genes (neural cell adhesion protein BIG2, heavy neurofilament subunit genes) in striatum and three genes (light neurofilament subunit, brain acyl-CoA synthetase II, heavy neurofilament subunit genes) in the SN. However three genes (N-acetylglucosaminyltransferase I, S100beta, and synaptonemal complex protein I genes) in striatum and six genes (noggin, striatin, Ost oncogene, S100beta, calcium/calmodulin-dependent protein kinase kinase beta, and N-acetylglucosaminyltransferase I genes) in SN were elevated following Mn exposure. Immunohistochemical study revealed that protein levels of S100beta also increased following Mn treatment. Activated astrocytes overexpressing S100beta are invariably and intimately associated with decreased expression of heavy and light neurofilament subunits which is a distinguishing feature of neurodegeneration by Mn exposure. All our findings suggested that neuronal degenerations occur in SN as well as striatum of mice exposed to Mn.