Peroxisome proliferator activated receptor gamma (PPARγ) antagonism inhibits ultraviolet radiation (UVR)‐induced apoptosis, proliferation, inflammation, and COX‐2 induction

We have previously shown that UVR induces PPAR γ agonist activity; PPARγactivation was also necessary for UVR‐stimulated cyclooxygenase (COX)‐2 induction. Objective: We hypothesized that PPARγ is necessary for early UVR‐induced apoptosis, inflammation, and delayed hyperproliferation. Methods: Albino, hairless SKH‐1 mice were pretreated topically with the selective and irreversible PPARγ antagonist, GW9662 (10 mM), prior to irradiation with 1500 J/m 2 of UVB. The mice were sacrificed at 24 & 72 hrs following UVR. Apoptosis was assessed by immunohistochemical detection of activated caspase 3 and sunburn cell formation. Proliferation was assessed by bromodeoxyuridine incorporation and mitotic figure counts. The inflammatory response was measured by changes in skin thickness. COX‐2 expression was assessed at 24 hrs by real‐time RT‐PCR. Results: PPARγ antagonism significantly blocked UVR‐induced apoptosis at 24 hrs, increased proliferation at 72 hrs, and increased skin thickness at 24 & 72 hrs. In addition, GW9662 inhibited UVR‐stimulated COX‐2 induction. Conclusion: These studies strongly suggest that PPARγ is an important mediator of epidermal photobiology & possibly photocarcinogenesis. This has important implications, given that PPARγ agonists (e.g. rosiglitazone) are in widespread use for the treatment of type II diabetes. Support: Clarian Values Fund Research Grant, Clarian Health Partners, Indianapolis, IN