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Prostaglandin E receptor type 4-associated protein interacts directly with NF-kappaB1 and attenuates macrophage activation.

Macrophage activation participates pivotally in the pathophysiology of chronic inflammatory diseases, including atherosclerosis. Through the receptor EP4, prostaglandin E(2) (PGE(2)) exerts an anti-inflammatory action in macrophages, suppressing stimulus-induced expression of certain proinflammatory genes, including chemokines. We recently identified a novel EP4 receptor-associated protein (EPRAP), whose function in PGE(2)-mediated anti-inflammation remains undefined. Here we demonstrate that PGE(2) pretreatment selectively inhibits lipopolysaccharide (LPS)-induced nuclear factor kappaB1 (NF-kappaB1) p105 phosphorylation and degradation in mouse bone marrow-derived macrophages through EP4-dependent mechanisms. Similarly, directed EPRAP expression in RAW264.7 cells suppresses LPS-induced p105 phosphorylation and degradation, and subsequent activation of mitogen-activated protein kinase kinase 1/2. Forced expression of EPRAP also inhibits NF-kappaB activation induced by various proinflammatory stimuli in a concentration-dependent manner. In co-transfected cells, EPRAP, which contains multiple ankyrin repeat motifs, directly interacts with NF-kappaB1 p105/p50 and forms a complex with EP4. In EP4-overexpressing cells, PGE(2) enhances the protective action of EPRAP against stimulus-induced p105 phosphorylation, whereas EPRAP silencing in RAW264.7 cells impairs the inhibitory effect of PGE(2)-EP4 signaling on LPS-induced p105 phosphorylation. Additionally, EPRAP knockdown as well as deficiency of NF-kappaB1 in macrophages attenuates the inhibitory effect of PGE(2) on LPS-induced MIP-1beta production. Thus, PGE(2)-EP4 signaling augments NF-kappaB1 p105 protein stability through EPRAP after proinflammatory stimulation, limiting macrophage activation.

Pubmed ID: 18270204

Authors

  • Minami M
  • Shimizu K
  • Okamoto Y
  • Folco E
  • Ilasaca ML
  • Feinberg MW
  • Aikawa M
  • Libby P

Journal

The Journal of biological chemistry

Publication Data

April 11, 2008

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL 34636

Mesh Terms

  • Amino Acid Motifs
  • Animals
  • Atherosclerosis
  • Bone Marrow Cells
  • Cell Cycle Proteins
  • Cell Line
  • Chemokines
  • Dinoprostone
  • Gene Silencing
  • Humans
  • Lipopolysaccharides
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Macrophage Activation
  • Macrophages
  • Mice
  • Mice, Knockout
  • NF-kappa B p50 Subunit
  • Phosphorylation
  • Protein Binding
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP4 Subtype
  • Signal Transduction