Prostaglandin D2 induces heme oxygenase-1 mRNA expression through the DP2 receptor

Prostaglandin (PG) D2 exerts multiple actions through interaction with distinct receptors, DP1 and DP2. We have shown that PGD2 induces the expression of heme oxygenase-1 (HO-1) in the retinal pigment epithelium (RPE) that is essential for survival of photoreceptors. HO-1 is a key enzyme in physiological heme degradation. Here, we explored the mechanism for the PGD2-mediated induction of HO-1 expression using ARPE-19 human RPE cells. ARPE-19 cells secrete PGD2 and express DP2 mRNA, but not DP1 mRNA. Treatment with a DP2 agonist, 15(R)-15-methyl-PGD2 or DK-PGD2, increased HO-1 mRNA expression, and pretreatment with a DP2 antagonist, CAY10471, decreased the magnitude of the PGD2-mediated HO-1 induction. By contrast, either DP1 agonist or antagonist caused only marginal influence on HO-1 expression. Moreover, transient expression assays showed the DP2 agonist activated the HO-1-gene promoter in the enhancer-dependent manner. Thus, PGD2 induces HO-1 mRNA expression through DP2 receptor, linking the PGD2-DP2 signaling with heme homeostasis.