title: Photo-oxidation products of skin surface squalene mediate metabolic and inflammatory responses to solar UV in human keratinocytes.
abstract: The study aimed to identify endogenous lipid mediators of metabolic and inflammatory responses of human keratinocytes to solar UV irradiation. Physiologically relevant doses of solar simulated UVA+UVB were applied to human skin surface lipids (SSL) or to primary cultures of normal human epidermal keratinocytes (NHEK). The decay of photo-sensitive lipid-soluble components, alpha-tocopherol, squalene (Sq), and cholesterol in SSL was analysed and products of squalene photo-oxidation (SqPx) were quantitatively isolated from irradiated SSL. When administered directly to NHEK, low-dose solar UVA+UVB induced time-dependent inflammatory and metabolic responses. To mimic UVA+UVB action, NHEK were exposed to intact or photo-oxidised SSL, Sq or SqPx, 4-hydroxy-2-nonenal (4-HNE), and the product of tryptophan photo-oxidation 6-formylindolo[3,2-b]carbazole (FICZ). FICZ activated exclusively metabolic responses characteristic for UV, i.e. the aryl hydrocarbon receptor (AhR) machinery and downstream CYP1A1/CYP1B1 gene expression, while 4-HNE slightly stimulated inflammatory UV markers IL-6, COX-2, and iNOS genes. On contrast, SqPx induced the majority of metabolic and inflammatory responses characteristic for UVA+UVB, acting via AhR, EGFR, and G-protein-coupled arachidonic acid receptor (G2A).
  
  
  CONCLUSIONS
  Our findings indicate that Sq could be a primary sensor of solar UV irradiation in human SSL, and products of its photo-oxidation mediate/induce metabolic and inflammatory responses of keratinocytes to UVA+UVB, which could be relevant for skin inflammation in the sun-exposed oily skin.
authors.affiliation: Laboratory of Tissue Engineering & Skin Pathophysiology, Istituto Dermopatico dell'Immacolata (IDI IRCCS), Rome, Italy.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kostyuk
authors.forename: Alla
authors.initials: A
authors.lastname: Potapovich
authors.forename: Andrea
authors.initials: A
authors.lastname: Stancato
authors.forename: Chiara
authors.initials: C
authors.lastname: De Luca
authors.forename: Daniela
authors.initials: D
authors.lastname: Lulli
authors.forename: Saveria
authors.initials: S
authors.lastname: Pastore
authors.forename: Liudmila
authors.initials: L
authors.lastname: Korkina
mesh_terms: D000328:Adult; D000447:Aldehydes / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004817:Epidermis / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000528:radiation effects; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D012867:Skin / Q000528:radiation effects*; D013185:Squalene / Q000494:pharmacology*; D013499:Surface Properties / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D014466:Ultraviolet Rays
chemical_list: C111855:6-formylindolo(3,2-b)carbazole; D000447:Aldehydes; D002227:Carbazoles; D016207:Cytokines; D007527:Isoenzymes; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013185:Squalene; D052247:Nitric Oxide Synthase Type II; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; C027576:4-hydroxy-2-nonenal