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Título

Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages

Autor Díaz-Muñoz, Manuel D.; Osma-García, Inés C.; Fresno, Manuel; Íñiguez, Miguel Ángel
Palabras clave Gene regulation
E-prostanoid (EP) receptor
Inflammation
Lipid mediator
Microsomal prostaglandin E synthase 1 (mPGES-1)
Cyclo-oxygenase-2 (COX-2)
Fecha de publicación 2012
EditorPortland Press
Citación Biochemical Journal 443: 451- 461 (2012)
ResumenPG (prostaglandin) E2 plays an important role in the modulation of the immune response and the inflammatory process. In the present study, we describe a PGE2 positive feedback for COX (cyclo oxygenase)-2 and mPGES-1 (microsomal PGES (PGE synthase)-1) expression in the macrophage cell line RAW 264.7. Our results show that PGE2 induces COX-2 and mPGES-1 expression, an effect mimicked by dbcAMP (dibutyryl-cAMP) or forskolin. Furthermore, the cAMP signalling pathway cooperates with LPS (lipopolysaccharide) in the induction of COX-2 and mPGES-1 transcriptional activation. Analysis of the involvement of PGE receptors (EPs (E-prostanoids)) showed that incubation with EP2 agonists up-regulated both COX2 and mPGES-1 mRNA levels. Moreover, EP2 receptor overexpression enhanced the transcriptional activation of COX2 and mPGES-1 promoters. This induction was repressed by the PKA (protein kinase A) inhibitor H89. Activation of the PGE2/EP2/PKA signalling pathway induced the phosphorylation of CREB (CRE (cAMP-response element)-binding protein) in macrophages and stimulated the specific binding of this transcription factor toCOX2 and mPGES-1 promoters. Deletion or mutation of potential CRE sites in both promoters diminished their transcriptional activity. In summary, the results of the present study demonstrate that activation of PKA/CREB signalling through the EP2 receptor by PGE2 plays a key role in the expression of COX-2 and mPGES-1 in activated macrophages
URI http://hdl.handle.net/10261/113629
DOI10.1042/BJ20111052
Identificadoresdoi: 10.1042/BJ20111052
issn: 1470-8728
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