Prostaglandin (PG) D(2) exerts multiple actions through interaction with distinct receptors, DP1 and DP2. We have shown that PGD(2) 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 PGD(2)-mediated induction of HO-1 expression using ARPE-19 human RPE cells. ARPE-19 cells secrete PGD(2) and express DP2 mRNA, but not DP1 mRNA. Treatment with a DP2 agonist, 15(R)-15-methyl-PGD(2) or DK-PGD(2), increased HO-1 mRNA expression, and pretreatment with a DP2 antagonist, CAY10471, decreased the magnitude of the PGD(2)-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, PGD(2) induces HO-1 mRNA expression through DP2 receptor, linking the PGD(2)-DP2 signaling with heme homeostasis.
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