title: Epidermal peroxisome proliferator-activated receptor gamma as a target for ultraviolet B radiation.
abstract: Ultraviolet B radiation (UVB) is a pro-oxidative stressor with profound effects on skin in part through its ability to stimulate cytokine production. Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to regulate inflammatory processes and cytokine release in various cell types. Since the oxidized glycerophospholipid 1-hexadecyl-2-azelaoyl glycerophosphocholine (azPC) has been shown to be a potent PPAR gamma agonist, this study was designed to assess whether the PPAR gamma system is a target for UVB irradiation and involved in UVB-induced inflammation in epidermal cells. The present studies demonstrated the presence of PPAR gamma mRNA and functional protein in human keratinocytes and epithelial cell lines HaCaT, KB, and A431. The treatment of epidermal cells with the PPAR gamma-specific agonist ciglitazone or azPC augmented cyclooxygenase-2 expression and enzyme activity induced by phorbol 12-myristate-13-acetate or interleukin-1 beta. Lipid extracts from the cell homogenate of UVB-irradiated, but not control, cells contained a PPAR gamma-agonistic activity identified by reporter assay, and this activity up-regulated cyclooxygenase-2 expression induced by phorbol 12-myristate-13-acetate. Subjecting purified 1-hexadecyl-2-arachidonoyl-glycerophosphocholine to UVB irradiation generated a PPAR gamma-agonistic activity, among which the specific PPAR gamma agonist azPC was identified by mass spectrometry. These findings suggested that UVB-generated PPAR gamma-agonistic activity was due to the free radical mediated non-enzymatic cleavage of endogenous glycerophosphocholines. Treatment with the specific PPAR gamma antagonist GW9662 or expression of a dominant-negative PPAR gamma mutant in KB cells inhibited UVB-induced epidermal cell prostaglandin E(2) production. These findings suggested that UVB-generated PPAR gamma activity is necessary for the optimal production of epidermal prostaglandins. These studies demonstrated that epithelial cells contain a functional PPAR gamma system, and this system is a target for UVB through the production of novel oxidatively modified endogenous phospholipids.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indinapolis, Indiana 46202, USA.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Zhang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Southall
authors.forename: Steven M
authors.initials: SM
authors.lastname: Mezsick
authors.forename: Christopher
authors.initials: C
authors.lastname: Johnson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Konger
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects*; D008565:Membrane Proteins; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism / Q000528:radiation effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014466:Ultraviolet Rays
chemical_list: D007375:Interleukin-1; D008565:Membrane Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; C437372:interleukin-1 delta; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D013755:Tetradecanoylphorbol Acetate; C039671:ciglitazone