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Prostaglandin E₂ Stimulates AP-1-Mediated CD14 Expression in Mouse Macrophages Via Cyclic AMP-Dependent Protein Kinase A¹

Department of Oral Microbiology, Meikai University School of Dentistry, Keyakidai, Sakado City, Saitama, Japan

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. PGE₁, PGE₂, and PGA₁ 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]-1H-indol-3-yl}-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione (GF109203X), abolished the stimulated expression of CD14. A run-on assay showed that PGE₂ stimulated the CD14 gene expression at the transcriptional level via protein kinase A. PGE₂ 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. PGE₂-stimulated expression of CD14 was inhibited by antisense c-fos and c-jun oligonucleotides, but not by their sense oligonucleotides. Finally, PGE₂ pretreatment synergistically stimulated LPS-induced expression of IL-1ß and IL-6 genes in mouse macrophages. Therefore, the present study demonstrates that PGE₂ has the ability to stimulate AP-1-mediated expression of CD14 in mouse macrophages via cAMP-dependent protein kinase A.

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