Photobiologic and photoimmunologic characteristics of XPA gene-deficient mice.
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.
Horio
T
T
Department of Dermatology, Kansai Medical University, Moriguchi, Osaka, Japan. horio@takii.kmu.ac.jp
Miyauchi-Hashimoto
H
H
Kuwamoto
K
K
Horiki
S
S
Okamoto
H
H
Tanaka
K
K
D000818:Animals; D001081:Apyrase / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D003877:Dermatitis, Contact / Q000209:etiology; D007165:Immunosuppression Therapy; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D007801:Langerhans Cells / Q000201:enzymology / Q000528:radiation effects; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D018462:Photobiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011453:Prostaglandins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011855:Radiodermatitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D013471:Sunburn / Q000209:etiology; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D011453:Prostaglandins; D012333:RNA, Messenger; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D001081:Apyrase; D007213:Indomethacin