Calcineurin inhibitors reduce nuclear localization of transcription factor NFAT in UV-irradiated keratinocytes and reduce DNA repair.
Calcineurin inhibitors are drugs used to suppress the immune system by blocking the nuclear localization of the NFAT transcription factor. Systemic use of these drugs is essential to organ transplantation, but comes at the cost of elevated rates of skin cancer. They have been used topically in atopic dermatitis and other skin diseases on the assumption that they avoid the cancer risk by localized use. The results here show that in skin cells and artificial models of human skin, calcineurin inhibitors block UV-induced nuclear localization of NFAT, and significantly reduce repair of cyclobutane pyrimidine dimers induced in DNA. In addition they inhibit apoptosis of UV-irradiated cells. The effect of blocking nuclear localization of NFAT and inhibiting DNA repair should be considered in judging the risk of topical use of calcineurin inhibitors.
Canning
Matthew T
MT
AGI Dermatics, 205 Buffalo Avenue, Freeport, NY 11520, USA. mcanning@agiderm.com
Nay
Stephanie L
SL
Peña
Arely V
AV
Yarosh
Daniel B
DB
D017209:Apoptosis; D065095:Calcineurin Inhibitors; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004260:DNA Repair; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011740:Pyrimidine Dimers / Q000235:genetics; D017768:Skin, Artificial; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D011740:Pyrimidine Dimers; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; C058028:immunomycin; D016559:Tacrolimus