? Ultraviolet B (UVB) exposure is the primary cause of cutaneous neoplasia and also is an effective treatment modality for inflammatory skin lesions like psoriasis. We have recently shown that UVB exposure is a potent activator of the ligand-activated transcriptional regulator, peroxisome proliferator activated receptor-gamma (PPARgamma). Thus, PPARgamma activation may play a key role in regulating UVBmediated cellular stress responses in the epidermis. In line with this idea, we have shown in two different cell lines, including primary keratinocytes (PHKs), that UVB mediated cyclooxygenase 2 (COX-2) induction is PPARgamma dependent. Moreover, we show that ciglitazone, a member of a commonly prescribed class of anti-diabetic PPARgamma agonists, is also capable of inducing COX-2 expression in PHKs. Given that UVB, COX-2, and PPARgamma have all been shown to independently alter cellular growth, differentiation, and apoptosis, we hypothesize that many of these UVB-mediated cellular stress responses may be due to PPARgamma activation, either in a COX-2 dependent or independent fashion. In line with this hypothesis, we provide evidence that PPARgamma alters keratinocyte differentiation and apoptosis. In this grant application, we propose to further define which of these UVB-mediated cellular stress responses are PPARgamma dependent. This will be done using both in vitro and in vivo models to examine how activation of PPARgamma alters cellular growth, differentiation and apoptosis. This will be done both in the context of UVB-mediated PPARgamma activation, as well activation of PPARgamma alone. The role of COX-2 induction in these processes will also be examined. These studies are particularly important given that recent studies indicate that several PPARgamma agonists commonly used to treat type II diabetes may have cancer chemopreventive activity and may also be effective anti-psoriatic agents. This data can then be used to focus future studies on determining whether the PPARgamma system augments or suppresses UVB photocarcinogenesis, as well as determine what role PPARgamma plays in UVB-mediated treatment of inflammatory skin disease. Given the increasing rates of type II diabetes and the need to treat these patients over the long term with PPARgamma agonists, it is particularly important to have a greater understanding of the role these agents play in UVB photocarcinogenesis. ? ? ?
