Cyclooxygenase-2 Inhibits UVB-Induced Apoptosis in Mouse Skin by Activating the Prostaglandin E2 Receptors, EP2 and EP4

Open Access
Publisher Website
Google Scholar
Abstract
Cyclooxygenase-2 (COX-2) is induced by UVB light and reduces UVB-induced epidermal apoptosis; however, the mechanism is unclear. Therefore, wild-type (WT) and COX-2−/− mice were acutely treated with UVB (5 kJ/m2), and apoptotic signaling pathways were compared. Following exposure, apoptosis was 2.5-fold higher in COX-2−/− compared with WT mice. Because prostaglandin E2 (PGE2) is the major UV-induced prostaglandin and manifests its activity via four receptors, EP1 to EP4, possible differences in EP signaling were investigated in WT and COX-2−/− mice. Following UVB exposure, protein levels of EP1, EP2, and EP4 were elevated in WT mice, but EP2 and EP4 levels were 50% lower in COX-2−/− mice. Activated cyclic AMP-dependent protein kinase (PKA) and Akt are downstream in EP2 and EP4 signaling, and their levels were reduced in UVB-exposed COX-2−/− mice. Furthermore, p-Bad (Ser136 and Ser155), antiapoptotic products of activated Akt and PKA, respectively, were significantly reduced in UVB-exposed COX-2−/− mice. To further study the roles of EP2 and EP4, UVB-exposed CD-1 mice were topically treated with indomethacin to block endogenous PGE2 production, and PGE2, the EP2 agonist (butaprost) or EP4 agonist (PGE1 alcohol), was applied. Indomethacin reduced PKA and Akt activation by ∼60%, but PGE2 and the agonists restored their activities. Furthermore, both agonists decreased apoptosis in COX-2−/− mice by 50%. The data suggest that COX-2–generated PGE2 has antiapoptotic roles in UVB-exposed mouse skin that involves EP2- and EP4-mediated signaling. [Cancer Res 2007;67(5):2015–21]