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C/Ebpß regulates microglial ptges expression and pge2 production

Autor Saura, Josep ; Straccia, Marco ; Dentesano, Guido ; Valente, Tony; Solà, Carme
Fecha de publicación jul-2012
Citación 8th FENS (2012)
ResumenWe have recently described that the transcription factor C/EBPß regulates pro-inflammatory gene expression in glial activation. Since the production of the inflammatory lipid mediator PGE2 is increased in activated glial cells, we have undertaken a study to analyze whether C/EBPß participates in the regulation of PGE2 synthesis enzymes in these cells. To this end gene expression and PGE2 production was compared between wild-type and C/EBPß -/- mice, both in vitro and in vivo. We have observed a robust effect of C/EBPß deficiency in the expression of PTGES (=mPGES1) in glial activation. Thus, PTGES expression and PGE2 production induced by LPS (100 ng/ml) +IFN?(0.1 ng/ml) in primary mixed glial cultures were abolished in the absence of C/EBPß. qChIP experiments revealed C/EBPß binding to the PTGES promoter after LPS+IFN? treatment and double immunofluorescence revealed that PTGES expression was of microglial origin. In line with this, marked LPS+IFN?-induced upregulation of PTGES expression was observed in microglial-enriched cultures and this was also abolished in the absence of C/EBPß. Systemic LPS injection (100 µg/mouse, i.p.) was used then to study neuroinflammation in vivo. This treatment upregulated PTGES mRNA levels in cerebral cortex and, as seen in vitro, the increase in PTGES expression was abolished in C/EBPß -/- mice. Interestingly, the expression of COX-2, another key enzyme in PGE2 synthesis, was also upregulated in glial activation in vitro and in vivo, but in contrast to PTGES, COX2 expression was barely affected by C/EBPß absence. Altogether these findings suggest that in microglial activation C/EBPß binds to the PTGES promoter, inducing its transcription. This leads to increased PTGES mRNA and protein levels and subsequent PGE2 accumulation. These findings strengthen the proposed role of C/EBPß as a key player in the orchestration of gene response in neuroinflammation.
Descripción Trabajo presentado al 8th Forum of Neuroscience (FENS) celebrado en Barcelona del 14 al 18 de julio de 2012.
URI http://hdl.handle.net/10261/92101
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