Augmentation of ultraviolet B radiation-induced tumor necrosis factor production by the epidermal platelet-activating factor receptor.

Lady C Dy,Jeffrey B Travers,Yong Pei

doi:10.1074/jbc.274.38.26917

Abstract

Ultraviolet B radiation (UVB) has been shown to damage human keratinocytes in part by inducing oxidative stress and cytokine production. Indeed, UVB-induced production of the pro-inflammatory and cytotoxic cytokine tumor necrosis factor alpha (TNF-alpha) has been implicated in the epidermal damage seen in response to acute solar radiation. Though the lipid mediator platelet-activating factor (PAF) is synthesized in response to oxidative stress, and keratinocytes express PAF receptors linked to cytokine biosynthesis, it is not known whether PAF is involved in UVB-induced epidermal cell cytokine production. These studies examined the role of the PAF system in UVB-induced epidermal cell TNF-alpha biosynthesis using a novel model system created by retroviral-mediated transduction of the PAF receptor-negative human epidermal cell line KB with the human PAF receptor (PAF-R). Treatment of PAF-R-expressing KB cells with the metabolically stable PAF-R agonist carbamoyl-PAF resulted in increased TNF-alpha mRNA and protein, indicating that activation of the epidermal PAF-R was linked to TNF-alpha production. UVB irradiation of PAF-R-expressing KB cells resulted in significant increases in both TNF-alpha mRNA and protein in comparison to UVB-treated control KB cells. However, UVB treatment up-regulated cyclooxygenase-2 mRNA levels to the same extent in both PAF-R-expressing and control KB cells. Pretreatment with the antioxidant vitamin E or the PAF-R antagonists WEB 2086 and A-85783 inhibited UVB-induced TNF-alpha production in the PAF-R-positive but not control KB cells. These studies suggest that the epidermal PAF-R may be a pharmacological target for UVB in skin.

Highlights

Ultraviolet B radiation (280 –320 nm; UVB) can have profound effects upon human keratinocytes
Using a model system our laboratory has developed by retroviralmediated gene transduction to express the human platelet-activating factor (PAF)-R in the PAF receptor (PAF-R)-negative human epidermoid cell line KB [24, 30], we present evidence indicating that the PAF-R can modulate UVB-induced TNF-␣ production, in part by the production of a soluble PAF-R agonistic activity that is structurally not PAF nor 1-acyl PAF
The Effects of CPAF on TNF-␣ Production in KB Cells—Our first studies assessed the ability of PAF-R activation to stimulate TNF-␣ production using the KBPAF-R model system

Summary

Introduction

Ultraviolet B radiation (280 –320 nm; UVB) can have profound effects upon human keratinocytes. Ultraviolet radiation-induced TNF-␣ production in keratinocytes has been implicated in UVB-induced inflammation and epidermal cell apoptosis [8]. In addition to its ability to induce the production of protein cytokines, ultraviolet radiation can induce the production of lipid mediators such as prostanoids and platelet-activating factor (1-alkyl-2-acetyl-glycero-3-phosphocholine (PAF)) in epidermal cells (9 –12). PAF is the best characterized ligand for the PAF-R; yet other natural products can bind to and signal through this receptor These other ligands include oxidized phospholipids derived from low density lipoproteins [19, 20], lipopolysaccharide and protein A [21], lipotechoic acid moieties on Streptococcus species [22], and 1-acyl-2-acetylglycerophosphocholines [23, 24]. Cytokines and the oxidative stress generated in response to UVB irradiation in epidermal cells can cause PAF production in other cell types [31,32,33]

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