Ultraviolet B radiation generates platelet-activating factor-like phospholipids underlying cutaneous damage.
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.
Marathe
Gopal K
GK
Human Molecular Biology and Genetics Program, University of Utah, Salt Lake City 84112-5330, USA. marathg@ccf.org
Johnson
Christopher
C
Billings
Steven D
SD
Southall
Michael D
MD
Pei
Yong
Y
Spandau
Dan
D
Murphy
Robert C
RC
Zimmerman
Guy A
GA
McIntyre
Thomas M
TM
Travers
Jeffrey B
JB
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D017690:Cell Transplantation; D002851:Chromatography, High Pressure Liquid; D000078404:Epidermal Cells; D004817:Epidermis / Q000528:radiation effects; D006801:Humans; D007249:Inflammation; D015603:Keratinocytes / Q000166:cytology / Q000528:radiation effects; D008024:Ligands; D008027:Light; D008055:Lipids / Q000737:chemistry; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D008956:Models, Chemical; D009504:Neutrophils / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010742:Phospholipid Ethers / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000528:radiation effects*; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry; D014466:Ultraviolet Rays; D014981:Xenopus
C091046:1-O-hexadecyl-2-desoxy-2-aminoarachidonoylglycero-3-phosphocholine; D008024:Ligands; D008055:Lipids; D010742:Phospholipid Ethers; D010743:Phospholipids; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D014443:Tyrosine; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D010100:Oxygen; D002118:Calcium