Abstract |
To date, oxidized glycerophosphocholines (Ox-GPCs) with platelet-activating factor (PAF) activity produced non-enzymatically have not been definitively demonstrated to mediate any known disease processes. Here we provide evidence that these Ox-GPCs play a pivotal role in the photosensitivity associated with the deficiency of the DNA repair protein xeroderma pigmentosum type A (XPA). It should be noted that XPA-deficient cells are known to have decreased antioxidant defenses. These studies demonstrate that treatment of human XPA-deficient fibroblasts with the pro-oxidative stressor ultraviolet B (UVB) radiation resulted in increased reactive oxygen species and PAF receptor (PAF-R) agonistic activity in comparison with gene-corrected cells. The UVB irradiation-generated PAF-R agonists were inhibited by antioxidants. UVB irradiation of XPA-deficient (Xpa-/-) mice also resulted in increased PAF-R agonistic activity and skin inflammation in comparison with control mice. The increased UVB irradiation-mediated skin inflammation and TNF-α production in Xpa-/- mice were blocked by systemic antioxidants and by PAF-R antagonists. Structural characterization of PAF-R-stimulating activity in UVB-irradiated XPA-deficient fibroblasts using mass spectrometry revealed increased levels of sn-2 short-chain Ox-GPCs along with native PAF. These studies support a critical role for PAF-R agonistic Ox-GPCs in the pathophysiology of XPA photosensitivity.
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Authors | Yongxue Yao, Kathleen A Harrison, Mohammed Al-Hassani, Robert C Murphy, Samin Rezania, Raymond L Konger, Jeffrey B Travers |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 287
Issue 12
Pg. 9311-21
(Mar 16 2012)
ISSN: 1083-351X [Electronic] United States |
PMID | 22303003
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Antioxidants
- Platelet Activating Factor
- Platelet Membrane Glycoproteins
- Reactive Oxygen Species
- Receptors, G-Protein-Coupled
- Tumor Necrosis Factor-alpha
- Xeroderma Pigmentosum Group A Protein
- Xpa protein, mouse
- platelet activating factor receptor
- Phosphorylcholine
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Topics |
- Animals
- Antioxidants
(metabolism)
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphorylcholine
(metabolism)
- Platelet Activating Factor
(agonists, metabolism)
- Platelet Membrane Glycoproteins
(agonists, genetics, metabolism)
- Radiation Tolerance
- Reactive Oxygen Species
(metabolism)
- Receptors, G-Protein-Coupled
(agonists, genetics, metabolism)
- Skin
(metabolism, radiation effects)
- Tumor Necrosis Factor-alpha
(metabolism)
- Ultraviolet Rays
- Xeroderma Pigmentosum
(genetics, metabolism)
- Xeroderma Pigmentosum Group A Protein
(genetics, metabolism)
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