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Musson, R.E.A.; Hensbergen, P.J.; Westphal, A.H.; Temmink, W.P.M.; Deelder, A.M.; Pelt, J. van; ... ; Smit, N.P.M. (2011)

UVA1 radiation inhibits calcineurin through oxidative damage mediated by photosensitization

Article / Letter to editor
The protein phosphatase calcineurin has been gradually revealing itself as the central controller of our immune response, although it is involved in a wide array of signaling pathways related to cellular development and cell cycle progression. As such, calcineurin is an attractive, yet delicate, therapeutic target for the prevention of allograft rejection and treatment of several inflammatory skin conditions. However, calcineurin activity is not only sensitive to immunosuppressants such as cyclosporin A and tacrolimus, but also subject to modulation by reactive oxygen species. We have recently shown, both in vivo and in vitro, that UVA1 radiation suppresses calcineurin activity. In this paper, we present evidence that this activity loss is due to singlet oxygen and superoxide generated by photosensitization and show that a closely related phosphatase, PP2A, is not affected. Furthermore, a survey of this damage reveals oxidation of several Met and Cys residues as well as an overall...Show moreThe protein phosphatase calcineurin has been gradually revealing itself as the central controller of our immune response, although it is involved in a wide array of signaling pathways related to cellular development and cell cycle progression. As such, calcineurin is an attractive, yet delicate, therapeutic target for the prevention of allograft rejection and treatment of several inflammatory skin conditions. However, calcineurin activity is not only sensitive to immunosuppressants such as cyclosporin A and tacrolimus, but also subject to modulation by reactive oxygen species. We have recently shown, both in vivo and in vitro, that UVA1 radiation suppresses calcineurin activity. In this paper, we present evidence that this activity loss is due to singlet oxygen and superoxide generated by photosensitization and show that a closely related phosphatase, PP2A, is not affected. Furthermore, a survey of this damage reveals oxidation of several Met and Cys residues as well as an overall conformational change. These findings provide a mechanistic basis for the hypothesis that UVA1 and calcineurin inhibitors both affect the same signal transduction pathway in skin. (C) 2011 Elsevier Inc. All rights reserved.Show less
Calcineurin Oxidative stress NFAT Skin Tacrolimus UVA radiation Free radicals singlet molecular-oxygen light-emission measurements transcription factor nfat human skin fibroblasts kappa-b activity hydrogen-peroxide cyclosporine-a ultraviolet-radiation phosphatase-activity human keratinocytes
All authors
Musson, R.E.A.; Hensbergen, P.J.; Westphal, A.H.; Temmink, W.P.M.; Deelder, A.M.; Pelt, J. van; Mullenders, L.H.F.; Smit, N.P.M.
Date
2011-05-15
Journal
Free Radical Biology and Medicine
Volume
50
Issue
10
Pages
1392 - 1399
DOI
doi:10.1016/j.freeradbiomed.2011.02.019