Ultraviolet A induces apoptosis via reactive oxygen species in a model for Smith-Lemli-Opitz syndrome.
Solar ultraviolet A (UVA) radiation induces many responses in skin including oxidative stress, DNA damage, inflammation, and skin cancer. Smith-Lemli-Opitz syndrome (SLO-S) patients show dramatically enhanced immediate (5 min) and extended (24-48 h) skin inflammation in response to low UVA doses compared to normal skin. Mutations in Delta7-dehydrocholesterol reductase, which converts 7-dehydrocholesterol to cholesterol, produces high levels of 7-dehydrocholesterol in SLO-S patient's serum. Since 7-dehydrocholesterol is more rapidly oxidized than cholesterol, we hypothesized that 7-dehydrocholesterol enhances UVA-induced oxidative stress leading to keratinocyte death and inflammation. When keratinocytes containing high 7-dehydrocholesterol and low cholesterol were exposed to UVA (10 J/cm2), eightfold greater reactive oxygen species (ROS) were produced than in normal keratinocytes after 15 min. UVA induced 7-dehydrocholesterol concentration-dependent cell death at 24 h. These responses were inhibited by antioxidants, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (diphenyleneiodonium) and a mitochondria-specific radical quencher. Cell death was characterized by activation of caspases-3, -8, and -9 and by phosphatidylserine translocation. Studies using antioxidants and specific caspase inhibitors indicated that activation of caspase-8, but not caspase-9, mediates ROS-dependent caspase-3 activation and suggested that ROS from NADPH oxidase activate caspase-8. These results support a ROS-mediated apoptotic mechanism for the enhanced UVA-induced inflammation in SLO-S patients.
Valencia
Antonio
A
Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Kochevar
Irene E
IE
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D003684:Dehydrocholesterols / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019082:Smith-Lemli-Opitz Syndrome / Q000378:metabolism / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*
D000975:Antioxidants; D003684:Dehydrocholesterols; D017382:Reactive Oxygen Species; C016705:7-dehydrocholesterol; D019255:NADPH Oxidases