PG (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 co-operates 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 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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Research Article|
March 27 2012
Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages
Manuel D. Díaz-Muñoz;
Manuel D. Díaz-Muñoz
1
1Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Princesa, Nicolás Cabrera 1, Cantoblanco, Universidad Autónoma de Madrid, 28049 Madrid, Spain
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Inés C. Osma-García;
Inés C. Osma-García
1Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Princesa, Nicolás Cabrera 1, Cantoblanco, Universidad Autónoma de Madrid, 28049 Madrid, Spain
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Manuel Fresno;
Manuel Fresno
2
1Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Princesa, Nicolás Cabrera 1, Cantoblanco, Universidad Autónoma de Madrid, 28049 Madrid, Spain
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Miguel A. Iñiguez
1Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Princesa, Nicolás Cabrera 1, Cantoblanco, Universidad Autónoma de Madrid, 28049 Madrid, Spain
3To whom correspondence should be addressed (email mainiguez@cbm.uam.es).
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Publisher: Portland Press Ltd
Received:
June 14 2011
Revision Received:
December 19 2011
Accepted:
January 23 2012
Accepted Manuscript online:
January 23 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (2): 451–461.
Article history
Received:
June 14 2011
Revision Received:
December 19 2011
Accepted:
January 23 2012
Accepted Manuscript online:
January 23 2012
Citation
Manuel D. Díaz-Muñoz, Inés C. Osma-García, Manuel Fresno, Miguel A. Iñiguez; Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. Biochem J 15 April 2012; 443 (2): 451–461. doi: https://doi.org/10.1042/BJ20111052
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