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J. Biol. Chem., Vol. 280, Issue 42, 35448-35457, October 21, 2005

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Ultraviolet B Radiation Generates Platelet-activating Factor-like Phospholipids underlying Cutaneous Damage^*

Gopal K. Marathe1, Christopher Johnson, Steven D. Billings¶, Michael D. Southall¶, Yong Pei¶, Dan Spandau¶, Robert C. Murphy, Guy A. Zimmerman, Thomas M. McIntyre||2, and Jeffrey B. Travers¶

From the Human Molecular Biology and Genetics Program and the ^||Department of Pathology, University of Utah, Salt Lake City, Utah 84112–5330, the ^¶Richard L. Roudebush Veteran's Administration Hospital, Indianapolis, the Department of Dermatology and H.B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana 46202, and the Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206

Ultraviolet B light (UVB) causes cutaneous inflammation and cell death, but the agents responsible are not defined. These studies examined the role of the platelet-activating factor (PAF) signaling system in UVB-mediated effects. Expression of the PAF receptor in the PAF receptor-negative epidermoid cell line KB augmented apoptosis in response to UVB irradiation. Overexpression of the PAF receptor in primary human keratinocytes also enhanced UVB-mediated apoptosis in vitro, and it enhanced apoptosis in an in vivo model of human keratinocytes grafted onto severe combined immune-deficient (SCID) mice. To define the mechanism by which UVB activates the PAF receptor, we used mass spectrometry to demonstrate significant amounts of the C₄ PAF analogs 1-alkyl-2-(butanoyl and butenoyl)-sn-glycero-3-phosphocholine, as well as native PAF in an epidermal cell line after UVB irradiation. Supplementing the cells with the precursor phospholipid 1-hexadecyl-2-arachidonoyl-sn-glycero-3-phosphocholine (HAPC) increased the amount of C₄ PAF analogs recovered after UVB exposure. We irradiated HAPC directly and found, even in the absence of a photosensitizer, fragmentation to C₄-PAF receptor ligands. We conclude UVB photo-oxidizes cellular phospholipids, creating PAF analogs that stimulate the PAF receptor to induce further PAF synthesis and apoptosis. PAF signaling may participate in the cutaneous inflammation that occurs during photo-aggravated dermatoses.

Received for publication, April 7, 2005 , and in revised form, August 17, 2005.

^* This work was supported by National Institutes of Health Grants HL44513 (to T. M. M.), AR01993 (to J. B. T.), HL62996 (to J. B. T.), and HL34303 (to R. C. M.) and by the Riley Memorial Association (to J. B. T.). 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.

² Present address: Dept. of Cell Biology, NC-10, Lerner Research Institute, 9500 Euclid Ave, Cleveland, OH 44195.

¹ To whom correspondence should be addressed. Present address: Dept. of Cell Biology, NC-10, Lerner Research Institute, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-1029; Fax: 216-444-9404; E-mail: marathg{at}ccf.org.

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