Prostaglandin E2 Stimulates AP-1-Mediated CD14 Expression in Mouse Macrophages Via Cyclic AMP-Dependent Protein Kinase A

PGs play a functional role in the early stage of Gram-negative bacterial infections, because this prostanoid is produced rapidly by epithelial cells after a bacterial infection. CD14, one of the LPS receptors, is a key molecule in triggering the response to bacterial LPS in association with a Toll-like molecule. Therefore, in this study, we investigated the effect of PG on CD14 expression in mouse macrophages. PGE 1 , PGE 2 , and PGA 1 among the PGs tested strongly stimulated the expression of the CD14 gene in the cells. The stimulatory action also was observed by Western blot analysis. cAMP-elevating agents stimulated expression of CD14 gene as well. Protein kinase A inhibitor, N -[2-( p -bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), but not protein kinase C inhibitor 3-{1-[3-(dimethylamino)propyl]-1 H -indol-3-yl}-4-(1 H -indol-3-yl)-1 H -pyrrole-2,5-dione (GF109203X), abolished the stimulated expression of CD14. A run-on assay showed that PGE 2 stimulated the CD14 gene expression at the transcriptional level via protein kinase A. PGE 2 also stimulated activation of AP-1, a heterodimer of c-Jun and c-Fos, because the prostanoid increased specific binding of nuclear proteins to the AP-1 consensus sequence and stimulated AP-1-promoted luciferase activity. PGE 2 -stimulated expression of CD14 was inhibited by antisense c- fos and c- jun oligonucleotides, but not by their sense oligonucleotides. Finally, PGE 2 pretreatment synergistically stimulated LPS-induced expression of IL-1β and IL-6 genes in mouse macrophages. Therefore, the present study demonstrates that PGE 2 has the ability to stimulate AP-1-mediated expression of CD14 in mouse macrophages via cAMP-dependent protein kinase A.