Prostaglandin E2 Promotes UV Radiation-Induced Immune Suppression through DNA Hypermethylation

Exposure of mice to UV radiation results in suppression of the contact hypersensitivity (CHS) response. Here, we report that the UV-induced suppression of CHS is associated with increases in the levels of cyclooxygenase-2 (COX-2), prostaglandin E-2 (PGE(2)), and PGE2 receptors in the exposed skin. UV radiation-induced suppression of CHS was inhibited by topical treatment of the skin with celecoxib or indomethacin (inhibitors of COX-2) or AH6809 (an EP2 antagonist). Moreover, mice deficient in COX-2 were found to be resistant to UV-induced suppression of CHS. The exposure of wild-typemice to UVB radiation resulted in DNA hypermethylation, increased DNA methyltransferase (Dnmt) activity, and elevated levels of Dnmt1, Dnmt3a, and Dnmt3b proteins in the skin, and these responses were downregulated on topical treatment of the site of exposure after irradiation with indomethacin or EP2 antagonist. Topical treatment of UVB-exposed COX-2-deficient mice with PGE(2) enhanced the UVB-induced suppression of CHS as well as global DNA methylation and elevated the levels of Dnmt activity and Dnmt proteins in the skin. Intraperitoneal injection of 5-aza-2'-deoxycytidine (5-Aza-dc), a DNA demethylating agent, restored the CHS response to 2,4-dinitrofluorobenzene in UVB-exposed skin and this was associated with the reduction in global DNA methylation and Dnmt activity and reduced levels of Dnmt proteins. Furthermore, treatment with 5-Aza-dc reversed the effect of PGE(2) on UV-induced suppression of CHS in COX-2-deficient mice. These findings reveal a previously unrecognized role for PGE(2) in the promotion of UVB-induced immunosuppression and indicate that it is mediated through PGE(2) regulation of DNA methylation.