Abstract
Prostaglandins (PGs) have been implicated in lowering intraocular pressure (IOP). A possible role of cyclooxygenase-2 (COX-2) in this process was emphasized by findings showing impaired COX-2 expression in the non-pigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. The present study investigates the effect of the major COX-2 product, PGE 2, on the expression of its synthesizing enzyme in human NPE cells (ODM-2). PGE 2 led to an increase of COX-2 mRNA and protein expression, whereas the expression of COX-1 remained unchanged. Upregulation of COX-2 expression by PGE 2 was accompanied by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK, and was abrogated by inhibitors of both pathways. Moreover, PGE 2-induced COX-2 expression was suppressed by the intracellular calcium chelator, BAPTA/AM, and the protein kinase C inhibitor bisindolylmaleimide II, whereas the protein kinase A inhibitor H-89 was inactive in this respect. Induction of COX-2 expression was also elicited by butaprost (EP 2 receptor agonist) and 11-deoxy PGE 1 (EP 2/EP 4 receptor agonist), but not by EP 1/EP 3 receptor agonists (17-phenyl-ω-trinor PGE 2, sulprostone). Consistent with these findings, the EP 1/EP 2 receptor antagonist, AH-6809, and the selective EP 4 receptor antagonist, ONO-AE3-208, significantly reduced PGE 2-induced COX-2 expression. Collectively, our results demonstrate that PGE 2 at physiologically relevant concentrations induces COX-2 expression in human NPE cells via activation of EP 2- and EP 4 receptors and phosphorylation of p38 and p42/44 MAPKs. Positive feedback regulation of COX-2 may contribute to the production of outflow-facilitating PGs and consequently to regulation of IOP.
Published Version
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