Platelet-activating factor receptor agonists mediate xeroderma pigmentosum a photosensitivity

Yongxue Yao, Kathleen A. Harrison, Mohammed Al-Hassani, Robert C. Murphy, Samin Rezania, Raymond Konger, Jeffrey Travers

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)9311-9321
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number12
DOIs
StatePublished - Mar 16 2012

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Xeroderma Pigmentosum
Photosensitivity
Platelet Activating Factor
Antioxidants
Irradiation
Fibroblasts
Xeroderma Pigmentosum Group A Protein
Skin
DNA Repair-Deficiency Disorders
Inflammation
platelet activating factor receptor
Mass spectrometry
Reactive Oxygen Species
Mass Spectrometry
Repair
Genes
Radiation
DNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Platelet-activating factor receptor agonists mediate xeroderma pigmentosum a photosensitivity. / Yao, Yongxue; Harrison, Kathleen A.; Al-Hassani, Mohammed; Murphy, Robert C.; Rezania, Samin; Konger, Raymond; Travers, Jeffrey.

In: Journal of Biological Chemistry, Vol. 287, No. 12, 16.03.2012, p. 9311-9321.

Research output: Contribution to journalArticle

Yao, Yongxue ; Harrison, Kathleen A. ; Al-Hassani, Mohammed ; Murphy, Robert C. ; Rezania, Samin ; Konger, Raymond ; Travers, Jeffrey. / Platelet-activating factor receptor agonists mediate xeroderma pigmentosum a photosensitivity. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 12. pp. 9311-9321.
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