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NFAT regulates induction of COX-2 and apoptosis of keratinocytes in response to ultraviolet radiation exposure

R. J. Flockhart^*, B. L. Diffey^*, P. M. Farr, J. Lloyd and N. J. Reynolds^*,1

^* Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; and

Department of Dermatology and

Department of Medical Physics, Royal Victoria Infirmary, Newcastle upon Tyne, UK

¹Correspondence: Institute of Cellular Medicine, Newcastle University, Framlington Pl., Newcastle upon Tyne NE2 4HH, UK. E-mail: n.j.reynolds{at}ncl.ac.uk

The nuclear factor of activated T cells (NFAT) transcription factors are regulated by calcium/calcineurin signals and play important roles in T cells, muscle, bone, and neural tissue. NFAT is expressed in the epidermis, and although recent data suggest that NFAT is involved in the skin’s responses to ultraviolet radiation (UVR), the wavelengths of radiation that activate NFAT and the biological function of UV-activated NFAT remain undefined. We demonstrate that NFAT transcriptional activity is preferentially induced by UVB wavelengths in keratinocytes. The derived action spectrum for NFAT activation indicates that NFAT transcriptional activity is inversely associated with wavelength. UVR also evoked NFAT2 nuclear translocation in a parallel wavelength-dependent fashion and both transcriptional activation and nuclear translocation were inhibited by the calcineurin inhibitor cyclosporin A. UVR also evoked NFAT2 nuclear translocation in three-dimensional skin equivalents. Evidence suggests that COX-2 contributes to UV-induced carcinogenesis. Inhibiting UV-induced NFAT activation in keratinocytes, reduced COX-2 protein induction, and increased UV-induced apoptosis. COX-2 luciferase reporters lacking functional NFAT binding sites were less responsive to UVR, highlighting that NFAT is required for UV-induced COX-2 induction. Taken together, these data suggest that the proinflammatory, antiapoptotic, and procarcinogenic functions of UV-activated COX-2 may be mediated, in part, by upstream NFAT signaling. Flockhart, R. J., Diffey, B. L., Farr, P. M., Lloyd, J., Reynolds, N. J. NFAT regulates induction of COX-2 and apoptosis of keratinocytes in response to ultraviolet radiation exposure.

Key Words: UVB • action spectrum • skin equivalents • cyclosporin A