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

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-2À/À 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-2À/À 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-2À/À 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-2À/À 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-2À/À mice. Furthermore, p-Bad (Ser 136 and Ser 155 ), antiapoptotic products of activated Akt and PKA, respectively, were significantly reduced in UVB-exposed COX-2À/À 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 f60%, but PGE 2 and the agonists restored their activities. Furthermore, both agonists decreased apoptosis in COX-2À/À mice by 50%. The data suggest that COX-2-generated PGE 2 has antiapoptotic roles in UVBexposed mouse skin that involves EP2-and EP4-mediated signaling. [Cancer Res 2007;67(5):2015-21]

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

“…Several studies have shown a link between prostaglandin production and the initiation and progression of skin carcinogenesis (Fischer et al, 1999;Wilgus et al, 2003;Chun et al, 2007). Our studies demonstrate that UVB also stimulates a number of additional synthases important in prostaglandin production, as well as prostaglandin receptors and each may be critical for mediating the biological effects of UVB in mouse skin (see Figure 11 for summary of prostaglandin synthase and prostaglandin receptor genes upregulated by UVB and those regulated by MAP kinases and/or PI3K).…”

“…PGE 2 receptors belong to a family of G-protein coupled receptors that function via distinct signaling mechanisms (Narumiya et al, 1999). All of the known receptors, including EP1 and EP2, are expressed in mouse skin and several have been directly linked to UVB-and phorbol ester-induced skin inflammation and carcinogenesis (Thompson et al, 2001;Sung et al, 2006;Brouxhon et al, 2007;Chun et al, 2007). Thus, UVB has previously been reported to stimulate expression of EP1, EP2 and EP4 in mouse skin, but to reduce expression of EP3 (Tober et al, 2007).…”

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

“…The effects of prostaglandins and the cross talk between prostaglandin receptors and their signaling intermediates are of intense interest because of the diverse effects of prostaglandins on cell growth, differentiation and carcinogenesis [3,38,[41][42][43]. While the effects of PGE 2 on epidermal keratinocytes are reasonably well understood [1,[43][44][45], there has been much less investigation in the effects of PGE 2 on human melanocytes.…”

“…While the effects of PGE 2 on epidermal keratinocytes are reasonably well understood [1,[43][44][45], there has been much less investigation in the effects of PGE 2 on human melanocytes. Several years ago we set out to determine the biologic effects of PGE 2 on human melanocytes, and showed that nanomolar concentrations of PGE 2 stimulated melanocyte dendricity [7].…”

Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects

“…A previous study demonstrated that COX-2 contains a PPRE in the promoter region and is a target for PPAR-mediated transactivation in epithelial cells 65 and immortalized keratinocytes 66 . Importantly, COX-2 induction has been implicated in UV-mediated processes ranging from carcinogenesis to local and systemic immunosuppression 29,30,[67][68][69] . Recent studies by our group demonstrate that cyclooxygenase-2 (COX-2) is a target of UVR-mediated PPARγ activation.…”