Photobiologic and Photoimmunologic Characteristics of XPA Gene-Deficient Mice

Abstract

Xeroderma pigmentosum group A (XPA) gene-deficient mice cannot repair UV-induced DNA damage and easily develop skin cancers by UV irradiation. Just like human XP patients, homozygous (-/-) mice developed stronger longer-lasting acute inflammation than did wild-type mice after a single irradiation with UVB. Moreover, the model mice showed more severe UV-induced damage of keratinocytes and Langerhans cells than did the control mice. UVB-induced local and systemic immunosuppression was greatly enhanced in the (-/-) mice. Treatment with indomethacin, an inhibitor of prostaglandin (PG) synthesis, inhibited UV-induced inflammation and abrogated immunosuppression. In XPA-deficient mice, the amount of PGE2 and the expression level of COX-2 mRNA greatly increased after UVB irradiation compared with wild-type mice. These results suggest that the excess DNA photoproducts remaining in XPA-deficient cells after UV radiation induce COX-2 expression and subsequently produce a high amount of PGE2, which causes the enhancement of inflammation and immunosuppression. In XPA-deficient mice, the natural killer cell activity significantly decreased after repeated exposures to UVB. Our experimental data indicate that cancer development in XP patients involves not only mutagenesis due to the defect in DNA repair, but also the enhanced UV-immunosuppression and intensified impairment of natural killer function.

Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity

“…As has been reported previously (55)(56)(57), UVB irradiation of XPA-deficient mice with a relatively low dose of UVB irradiation resulted in increased skin inflammation as measured by ear thickness in comparison with control mice. The present studies demonstrate that this abnormal UVB inflammatory response in XPA-deficient mice was susceptible to systemic treatment with the antioxidant vitamin C at doses that have been previously reported to block the formation of PAF-R agonists in blood following exposure to the potent pro-oxidative stressor cigarette smoke (35).…”

“…UVB Irradiation-mediated Exaggerated Skin Inflammation in XPA-deficient Mice Involves ROS and PAF Agonists-Humans deficient in XPA exhibit profound photosensitivity, and this feature has been faithfully replicated in XpaϪ/Ϫ mice (55)(56)(57). Given that PAF is a potent stimulator of skin inflammation (38,58,59), the next studies were designed to assess the role of the PAF system in the photosensitivity exhibited by XpaϪ/Ϫ mice.…”

Cyclooxygenase 2 selective inhibitors in cancer treatment and prevention

“…Also, the overexpression of COX-2 in transgenic mice sensitises their skin to carcinogens [65,66]. In addition, COX-2 levels are known to increase in xeroderma pigmentosum group A (XPA) gene-deficient mice following exposure to UV-B [113]. The precursor lesion, actinic keratosis (AK), gives rise to ∼ 60% of squamous cell carcinoma [107].…”

Anti-Inflammatory Role of Langerhans Cells and Apoptotic Keratinocytes in Ultraviolet-B–Induced Cutaneous Inflammation

“…Xeroderma pigmentosum A gene-deficient mice, an animal model of xeroderma pigmentosum, cannot repair UV-induced DNA damage, including CPD and 6-4PP formation, and they develop severe UVB-induced cutaneous inflammation (24). To examine the relationship between LCs and repair of UV-induced DNA damage, immunohistochemical staining for CPD and 6-4PP was performed at 5 min or 24 h after irradiation of Lang-DTR-EGFP mice with a single dose of UVB (2.5 kJ/m 2 ), with or without DT pretreatment (17,19).…”