期刊
BIOCHEMICAL JOURNAL
卷 443, 期 -, 页码 451-461出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20111052
关键词
cyclo-oxygenase-2 (COX-2); E-prostanoid (EP) receptor; gene regulation; inflammation; lipid mediator; microsomal prostaglandin E synthase 1 (mPGES-1)
资金
- Comunidad Autonoma de Madrid (CAM) [S-SAL-0159-2006]
- Cardiovascular Network (RECAVA) of the Instituto de Salud Carlos III [RD06/0014/1013]
- European EICOSANOX [LSH-CT-2004-005033]
- CAM-Universidad Autonoma de Madrid [CCG08-UAM/BIO-4299]
- Ministerio de Ciencia e Innovacion [SAF2007-61716, SAF2010-18733, BFU2007-62659/BMC, BFU2010-21055]
- Fundacion Ramon Areces
PG (prostaglandin) E-2 plays an important role in the modulation of the immune response and the inflammatory process. In the present study, we describe a PGE(2) 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 PGE(2) 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 PGE(2)/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 to COX2 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.
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