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NF-E2-related factor 2 regulates the stress response to UVA-1-oxidized phospholipids in skin cells

Florian Gruber^*,, Herbert Mayer, Barbara Lengauer^*, Veronika Mlitz^*, John M. Sanders, Alexandra Kadl, Martin Bilban, Rainer de Martin, Oswald Wagner, Thomas W. Kensler^||, Masayuki Yamamoto^¶, Norbert Leitinger^,1 and Erwin Tschachler^*,#

^* Department of Dermatology,

Department of Vascular Biology and Thrombosis Research, and

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria;

Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA;

^|| Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA;

^¶ University of Tsukuba, Tsukuba, Japan; and

^# Centre de Recherches et d’Investigations Epidermiques et Sensorielles, Neuilly, France

¹ Correspondence: Cardiovascular Research Center, University of Virginia, PO Box 801394, Charlottesville, VA 22908, USA. E-mail: nl2q{at}virginia.edu

Long-wavelength ultraviolet (UVA-1) radiation causes oxidative stress that modifies cellular molecules. To defend themselves against noxious oxidation products, skin cells produce detoxifying enzymes and antioxidants. We have recently shown that UVA-1 oxidized the abundant membrane phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), which then induced the stress-response protein heme oxygenase 1 (HO-1) in dermal fibroblasts. Here we examined the effects of UVA-1- and UV-oxidized phospholipids on global gene expression in human dermal fibroblasts and keratinocytes. We identified a cluster of genes that were coinduced by UVA-1-oxidized PAPC and UVA-1 radiation. The cluster included HO-1, glutamate-cysteine ligase modifier subunit, aldo-keto reductases-1-C1 and -C2, and IL-8. These genes are members of the cellular stress response system termed "antioxidant response." Accordingly, the regulatory regions of all of these genes contain binding sites for NF-E2-related factor 2 (NRF2), a major regulator of the antioxidant response. Both UVA-1 irradiation and treatment with oxidized lipids led to increased nuclear accumulation and DNA binding of NRF2. Silencing and deficiency of NRF2 suppressed the antioxidant response. Taken together, our data show that UVA-1-mediated lipid oxidation induces expression of antioxidant response genes, which is dependent on the redox-regulated transcription factor NRF2. Our findings suggest a different view on UV-generated lipid mediators that were commonly regarded as detrimental.—Gruber, F., Mayer, H., Lengauer, B., Mlitz, V., Sanders, J. M., Kadl, A., Bilban, M., de Martin, R., Wagner, O., Kensler, T. W., Yamamoto, M., Leitinger, N., Tschachler, E. NF-E2-related factor 2 regulates the stress response to UVA-1-oxidized phospholipids in skin cells.

Key Words: lipid oxidation • antioxidant response • redox-sensitive transcription • long-wavelength ultraviolet • phototherapy