Prostaglandin E2 downregulates interleukin‐12 production through EP4 receptors in human monocytes stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans and interferon‐γ

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Abstract
In the present study, we examined the effect of prostaglandin (PG) E2 on interleukin (IL) ‐12 production in monocytes stimulated with a combination of lipopolysaccharide (LPS) from Actinobacillus actinomycetemcomitans and interferon‐γ (A. actinomycetemcomitans‐LPS/IFN‐γ). Indomethacin, a cyclooxygenase inhibitor, enhanced IL‐12 production, but inhibited PGE2 generation in A. actinomycetemcomitans‐LPS/IFN‐γ‐stimulated monocytes. Exogenous PGE2 inhibited IL‐12 release in the cells. EP2, EP3 and EP4 receptor mRNA expression was detected in monocytes by reverse transcription‐polymerase chain reaction. 11‐deoxy‐PGE1 (an EP2/EP4 agonist) inhibited IL‐12 production in A. actinomycetemcomitans‐LPS/IFN‐γ‐challenged monocytes, whereas butaprost (an EP2 agonist) or ONO‐AP‐324 (an EP3 agonist) had no effect on IL‐12 production. Dibutyryl cAMP, a cAMP analogue, and forskolin, an adenylate cyclase activator, mimicked depression of IL‐12 production by PGE2. From these results, we suggest that PGE2 inhibits IL‐12 production via EP4 receptors by cAMP‐dependent pathways in A. actinomycetemcomitans‐LPS/IFN‐γ‐challenged monocytes.