Abstract 1275: Prostaglandin E2 promotes ultraviolet radiation-induced suppression of immune system in mice via DNA hypermethylation.

Abstract Excessive exposure of skin to solar ultraviolet (UV) radiation is known to suppress the immune system and UV-induced immunosuppression has been implicated in the promotion of the risk of skin cancer. This notion is further verified by the fact that chronically immune-suppressed patients who live in regions of intense sun exposure have an exceptionally high rate of skin cancer. To identify the molecular targets responsible for UV-induced immunosuppression, further studies were conducted. We have found that exposure of the C3H/HeN mouse skin with UV radiation (150 mJ/cm2) for 4 consecutive days resulted in suppression of contact hypersensitivity (CHS) response, which is considered to be a prototypic of T-cell mediated immune response, and suppression of CHS was associated with the enhancement in the expression levels of cyclooxygenase-2 (COX-2) and prostaglandin (PG) E2 production. Topical treatment of mice with celecoxib (500 μg) or indomethacin (50 μg), inhibitors of COX-2, or AH6809 (25 μg), an antagonist of PGE2, inhibits UV radiation-induced suppression of CHS. The mice deficient in COX-2 on C3H/HeN background are resistant to UV-induced suppression of CHS response to a contact sensitizer. Exposure of C3H/HeN mice with UVB radiation (150 mJ/cm2) for 4 consecutive days resulted in DNA hypermethylation, increase in DNA methyltransferase (Dnmt) activity, and elevated levels of Dnmt1, Dnmt3a and Dnmt3b in epidermal skin samples, while treatment of mice with PGE2 antagonist or indomethacin before and during UVB exposure down-regulated the levels of DNA methylation as well as Dnmt activity compared to the mice which were not treated with PGE2 antagonist or indomethacin. Treatment of UV exposed COX-2-deficient mice with PGE2 (150 μg in 100μl/mouse/day) results in UV-induced suppression of CHS, increase in DNA methylation, Dnmt activity and the levels of Dnmt1, Dnmt3a and Dnmt3b were elevated in the skin. Treatment of C3H/HeN mice with 5-aza-2’-deoxycytidine (5-aza-dc, 1.0 mg/kg body weight, i.p.), a DNA demethylating agent or an inhibitor of DNA methylation, 1 h before each exposure of UV irradiation resulted in inhibition of UVB-induced suppression of CHS which was associated with the reduction in Dnmt activity, global DNA methylation and reduced levels of Dnmt1, Dnmt3a and Dnmt3b proteins compared to the mice which were not treated with 5-aza-dc but exposed to UV. Further, treatment of 5-aza-dc reversed the effect of PGE2 on UV-induced suppression of CHS response in COX-2-deficient mice. These findings uncover a previously unrecognized role of PGE2 in the promotion of UVB-induced suppression of CHS response and that it is mediated through DNA methylation. Citation Format: Ram Prasad, Santosh K. Katiyar. Prostaglandin E2 promotes ultraviolet radiation-induced suppression of immune system in mice via DNA hypermethylation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1275. doi:10.1158/1538-7445.AM2013-1275