apyrase and Sunburn

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.

Topics: Animals; Apyrase; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dermatitis, Contact; DNA-Binding Proteins; Immunosuppression Therapy; Indomethacin; Isoenzymes; Killer Cells, Natural; Langerhans Cells; Lymphocyte Count; Mice; Mice, Knockout; Photobiology; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Radiodermatitis; RNA, Messenger; Sunburn; Ultraviolet Rays; Xeroderma Pigmentosum Group A Protein

Xeroderma pigmentosum group A (XPA) gene-deficient mice were developed by gene targeting in mouse embryonic stem cells. To examine whether these XPA-model mice display photodermatologic abnormalities similar to those in human xeroderma pigmentosum, we investigated the effects of acute ultraviolet radiation on the homozygous (-/-) mice compared to the wild type (+/+) and heterozygous (+/-) mice. A single irradiation with ultraviolet B or topical psoralen plus ultraviolet A treatment induced stronger and longer lasting ear swelling in the (-/-) mice than in the (+/+) and (+/-) mice. Histologic changes including epidermal necrosis, cell infiltration, and sunburn cell formation after ultraviolet B radiation were more prominent in the (-/-) model mice than in the control mice. The (-/-) model mice showed damage of ADPase(+)Langerhans cells at a lower ultraviolet B dose than did the control mice. Moreover, the reappearance of ADPase(+)Langerhans cells after ultraviolet B radiation was delayed in the (-/-) mice compared to the control mice. Although contact hypersensitivity was induced equally in all mice, ultraviolet B-induced local and systemic immunosuppression were greatly enhanced in the (-/-) model mice. The data suggest that the XPA gene-deficient mice may be a useful model of human XPA, because the responses to UV radiation in the mice were very similar to those in the patients with XPA. Moreover, it is possible that enhanced ultraviolet immunosuppression is involved in the development of skin cancers in xeroderma pigmentosum.

Topics: Animals; Apyrase; Dermatitis, Contact; Immunosuppression Therapy; Langerhans Cells; Mice; Mice, Mutant Strains; PUVA Therapy; Skin; Sunburn; Ultraviolet Rays; Xeroderma Pigmentosum

Langerhans cells (LCs) are epidermal antigen-presenting cells capable of initiating a specific T lymphocyte-mediated immune response. It is a well known fact that ultraviolet light B (UVB) suppresses LC number and function. In this study, we confirmed that the sunscreens CITY BLOCK, and TOTAL SUN SHIELD 28 (Clinique Laboratories Tokyo, Japan) protected the epidermis against the depletion of LC number. We also investigated whether or not sunscreens could provide LC protection from ultraviolet ray (UVR) damage other than the prevention of the decrease in the total number of cells. Our data showed that the LC population was depressed after irradiation by 100 mJ/cm2 or 10 mJ/cm2 of UVB, but recovered to within normal levels after 16 days. Both sunscreens provided protection against erythema and LC depression due to UVB irradiation. However, despite the fact that these sunscreens had completely suppressed UVB erythema, shrinkage of LC dendrites was seen. Apparently, sunscreens prevent UVB erythema, but do not protect against functional changes in LC due to UVB. Recently, it has been reported that sunscreens are less effective in protecting against systemic immunosuppression that against inflammation. The shrinkage of LC dendrites despite sunscreen application may help explain this discrepancy.

Topics: Animals; Apyrase; Cell Count; Erythema; Langerhans Cells; Male; Mice; Mice, Inbred Strains; Sunburn; Sunscreening Agents; Ultraviolet Rays