Photooxidation generates biologically active phospholipids that induce heme oxygenase-1 in skin cells.
Heme oxygenase-1 (HO-1) is a key enzyme in the cellular response to tissue injury and oxidative stress. HO-1 enzymatic activity results in the formation of the cytoprotective metabolites CO and biliverdin. In the skin, HO-1 is strongly induced after long wave ultraviolet radiation (UVA-1). Here we show that UVA-1 irradiation generates oxidized phospholipids derived from 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) that mediate the expression of HO-1 in skin cells. Using EO6 antibodies that recognize oxidized phospholipids, we show that UVA-1 irradiation of dermal fibroblasts generates oxidation-specific epitopes. Irradiation of arachidonate-containing phospholipids with UVA-1 led to formation of defined lipid oxidation products including epoxyisoprostane-phosphatidylcholine that induced HO-1 expression in dermal fibroblasts, in keratinocytes, and in a three-dimensional epidermal equivalent model. In addition, we demonstrate that the oxidation of PAPC by UVA-1 is a singlet oxygen-dependent mechanism. Together, we present a novel mechanism of UVA-1-induced HO-1 expression that is mediated by the generation of biologically active phospholipid oxidation products. Because UVA-1 irradiation is a mainstay treatment of several inflammatory skin diseases, structural identification of UVA-1-generated biomolecules with HO-1-inducing capacity should lead to the development of drugs that could substitute for irradiation.
Gruber
Florian
F
Deparment of Dermatology, Medical University of Vienna, Vienna 1090, Austria.
Oskolkova
Olga
O
Leitner
Alexander
A
Mildner
Michael
M
Mlitz
Veronika
V
Lengauer
Barbara
B
Kadl
Alexandra
A
Mrass
Paul
P
Krönke
Gerhard
G
Binder
Bernd R
BR
Bochkov
Valery N
VN
Leitinger
Norbert
N
Tschachler
Erwin
E
D001483:Base Sequence; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D017931:DNA Primers; D004790:Enzyme Induction; D000939:Epitopes / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000528:radiation effects*; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000276:immunology / Q000378:metabolism*; D026082:Singlet Oxygen; D014466:Ultraviolet Rays
D017931:DNA Primers; D000939:Epitopes; D010743:Phospholipids; D026082:Singlet Oxygen; D006419:Heme Oxygenase (Decyclizing)