NF-E2-related factor 2 regulates the stress response to UVA-1-oxidized phospholipids in skin cells.
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
Florian
F
Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Mayer
Herbert
H
Lengauer
Barbara
B
Mlitz
Veronika
V
Sanders
John M
JM
Kadl
Alexandra
A
Bilban
Martin
M
de Martin
Rainer
R
Wagner
Oswald
O
Kensler
Thomas W
TW
Yamamoto
Masayuki
M
Leitinger
Norbert
N
Tschachler
Erwin
E
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D015870:Gene Expression / Q000528:radiation effects; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family / Q000528:radiation effects; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000528:radiation effects; D010743:Phospholipids / Q000378:metabolism* / Q000528:radiation effects*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D014466:Ultraviolet Rays
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D010743:Phospholipids; D034741:RNA, Small Interfering; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase