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  • Title: Cyclooxygenase-2 inhibits UVB-induced apoptosis in mouse skin by activating the prostaglandin E2 receptors, EP2 and EP4.
    Author: Chun KS, Akunda JK, Langenbach R.
    Journal: Cancer Res; 2007 Mar 01; 67(5):2015-21. PubMed ID: 17332329.
    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/m(2)), and apoptotic signaling pathways were compared. Following exposure, apoptosis was 2.5-fold higher in COX-2-/- compared with WT mice. Because prostaglandin E(2) (PGE(2)) 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 (Ser(136) and Ser(155)), 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 PGE(2) production, and PGE(2), the EP2 agonist (butaprost) or EP4 agonist (PGE(1) alcohol), was applied. Indomethacin reduced PKA and Akt activation by approximately 60%, but PGE(2) and the agonists restored their activities. Furthermore, both agonists decreased apoptosis in COX-2-/- mice by 50%. The data suggest that COX-2-generated PGE(2) has antiapoptotic roles in UVB-exposed mouse skin that involves EP2- and EP4-mediated signaling.
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