Estudio de las acciones de la prostaglandina F2 alfa y de los glucocorticoides sobre la activación de linfocitos T
Author
Cacheiro Llaguno, CristinaEntity
UAM. Departamento de Biología Molecular; ; Centro de Biología Molecular Severo Ochoa (CBM)Date
2010-03-18Subjects
Linfocitos T-Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 18-03-2010Abstract
Cyclooxygenase (COX) is the enzyme responsible for the conversion of arachidonic acid to prostaglandin PGH2, which is further metabolized by a series of downstream synthases to the prostanoids. Indeed, the expression of the particular downstream enzyme and its coupling either to constitutively expressed COX-1 or to inducible COX-2 will determine the profile and levels of arachidonic metabolites released by cells. In T cells, it has been shown that transcriptional induction of COX-2 occurs early after T cell receptor triggering, suggesting functional implications of COX-2 activity in this process. However, little is known about the expression of terminal prostanoid synthases in T cells. Therefore, in the present study, we analized the expression of these enzymes in activated T cells and characterized the profile of prostanoid production. Our results show an up-regulated PGE2 and PGF2α production and a concomitant up-regulated expression of the prostaglandin F synthase whereas up-regulated expression of any of the PGE2 synthases was not observed. Because the role of PGE2 in T cells has been extensively studied, we focused on the role of prostaglandin F2α showing that this prostaglandin, upon binding to its receptor (FP), is able to induce the expression of proinflammatory genes involved in T cell activation, including COX-2 and several cytokines. In addition, we show that PGF2α activates the NFAT transcription factor that plays an essential role in the regulation of these genes in T cells. It is well known that optimal NFAT activation requires low sustained increases of [Ca2+i]. Accordingly, our results suggest the involvement of signalling triggered by Gq -coupled receptors as FP in the activation of NFAT and the induction of the expression of NFAT–dependent genes. Another aim of this work has been to analyze the anti-inflammatory properties of GCs in T lymphocytes. Our results show that the synthetic GC Dexamethasone (Dex) decreased the expression of pro-inflammatory genes as COX-2. This effect took place also at the transcriptional level, since this drug decreased the induction of the promoter activity of these genes. Studies with the promoter region of COX-2 have determined that inhibition of COX-2 transcriptional induction in T cells by Dex/GR is due to transcriptional interference with NFAT mediated activation of COX-2 promoter. Our results are suggestive for the existence of protein-protein interactions between activated GR and NFAT within the nuclear environment, what mediates interference with NFAT-dependent transactivation of several genes implicated in T cell activation. These interactions are mediated by glucocorticoid binding to the GR but are independent of the presence of a functional DBD in this receptor. On the other hand, Dex induced the mRNA levels of haematopoietic prostaglandin D synthase (hPGDS) and peroxisome proliferator-activated receptor (PPAR), being both considered anti-inflammatory genes. The observed effects are dependent on the presence of the GC receptor (GR). These results can explain some of the anti-inflammatory properties of GCs, not only through their inhibitory actions on pro-inflammatory genes but also through the induction of anti-inflammatory genes as hPGDS and PPAR.
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