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N. Guo, S. Feldon, R. Phipps; Prostaglandin D2 Stimulates Hyaluronan Synthesis Through the DP1 Receptor in Human Orbital Fibroblasts. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1454.
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Thyroid Eye Disease (TED) is characterized by infiltration of white blood cells and accumulation of nonsulfated glycosaminoglycan hyaluronan (HA) in orbital tissue. Recently, several studies provided evidence that prostaglandins (PG) are involved in TED. PGD2 has been considered to be both a pro- and anti-inflammatory mediator, acting via the PGD2 receptors DP1 and DP2. PGD2 has a variety of roles in vivo. It causes vasodilation, bronchoconstriction, and chemoattraction of eosinophils and T-cells. However, the role, if any, of PGD2 in TED remains unknown. Here, we study the effects of PGD2 on HA synthesis in orbital fibroblasts.
Primary orbital fibroblasts were isolated from individual Graves’ patients undergoing orbital decompression surgery. The cells were grown in RPMI media containing 10% FBS. DP1 and DP2 steady state mRNA levels were quantified by real time RT-PCR. We studied the effects of PGD2 selective agonists (DP1: BW245C; DP2: 15d-PGD2) and antagonists (DP1: MK0524; DP2: Ramatroban) on HA synthesis. The amount of HA in the cell culture supernatant was measured by HA ELISA.
We found that treatment of human orbital fibroblasts with PGD2 (0.5-5µM) stimulated HA synthesis and the level of all 3 types of HA Synthase (HAS) mRNA in a dose- and time-dependent manner. RT-PCR revealed that the DP1 receptor was expressed on orbital fibroblasts, while the DP2 receptor expression was barely detectable. BW245C, the selective DP1 agonist strongly induced HA synthesis, while the DP2 agonist 15d-PGD2 failed to induce HA synthesis or HAS mRNA. The DP1 antagonist MK0524 completely blocked PGD2 induced HA synthesis, while the DP2 antagonist Ramatroban did not.
We report that PGD2 is a potent inducer of HA synthesis and HAS activation in orbital fibroblasts through the DP1 signaling pathway.
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