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Ultraviolet B Radiation Generated Platelet-Activating Factor Receptor Agonist Formation Involves EGF-R-Mediated Reactive Oxygen Species¹

Yongxue Yao^*, Jay E. Wolverton^*, Qiwei Zhang^*, Gopal K. Marathe, Mohammed Al-Hassani^*, Raymond L. Konger^*, and Jeffrey B. Travers^2,*,

^* Departments of Dermatology, Pediatrics and the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry, University of Mysore, Manasagangothri, Mysore, India; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Pharmacology and Toxicology, Indiana University School of Medicine, and the Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202

Recent studies have implicated the lipid mediator platelet-activating factor (PAF) in UVB-mediated systemic immunosuppression known to be a major cause for skin cancers. Previously, our group has demonstrated that UVB irradiation triggers the production of PAF and oxidized glycerophosphocholines that act as PAF-receptor (PAF-R) agonists. The present studies explored the mechanisms by which UVB generates PAF-R agonists. UVB irradiation of human epidermal KB cells resulted in both increased levels of reactive oxygen species (ROS) and PAF-R agonistic activity. Pretreatment of KB cells with antioxidants vitamin C and N-acetylcysteine or the pharmacological inhibitor PD168393 specific for the epidermal growth factor receptor all inhibited UVB-induced ROS as well as PAF-R agonists, yet had no effect on fMLP-mediated PAF-R agonist production. In addition, in vivo production of PAF-R agonists from UVB-irradiated mouse skin was blocked by both systemic vitamin C administration and topical PD168393 application. Moreover, both vitamin C and PD168393 abolished UVB-mediated but not the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine-mediated immunosuppression as measured by the inhibition of delayed type contact hypersensitivity to the chemical dinitrofluorobenzene. These studies suggest that UVB-induced systemic immunosuppression is due to epidermal growth factor receptor-mediated ROS which results in PAF-R agonist formation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants R01HL062996 (to J.B.T.) and U19A1070448 539 (to J.B.T.), and a Veterans Affairs Merit Award Grant (to J.B.T.). J.E.W. was supported by the Riley Memorial Foundation.

² Address correspondence and reprint requests to Dr. Jeffrey B. Travers, H.B. Wells Center for Pediatric Research, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children Room 2659, 702 Barnhill Drive, Indianapolis, Indiana 46202. E-mail address: jtravers{at}iupui.edu

³ Abbreviations used in this paper: DNFB, dinitrofluorobenzene; PAF, platelet-activating factor; GPC, glycerophosphocholine; PAF-R, PAF receptor; PAF-AH, PAF-acetylhydrolase; ROS, reactive oxygen species; EGF-R, epithelial growth factor-receptor; NAC, N-acetylcysteine; DPI, diphenylene iodinium; CHS, contact hypersensitivity; CPAF, 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine.