Possible involvement of enhanced prostaglandin E-2 production in the photosensitivity in xeroderma pigmentosum group A model mice

Xeroderma pigmentosum group A (XPA) gene-deficient mice cannot repair UV-in duced DNA damage and easily develop skin cancers by UV irradiation. Therefo re, XPA-deficient mice are a useful model of human XP and represent a promi sing tool for photobiologic studies of the disorder, Exposure to ultraviole t (UV) B (280-320 nm) radiation greatly enhanced inflammation and immunosup pression in these mice. To investigate the molecular mechanisms of enhanced UV inflammation and immunosuppression, we determined the amount of prostag landin (PG) E-2, an inflammatory mediator and immunomodulator, and analysed the expression of cyclooxygenase (COX) mRNA in the ear skin of XPA-deficie nt mice after UV irradiation. In XPA-deficient mice, the amount of PGE(2) s ignificantly increased at 48 and 72 h after UVB irradiation to the level th at was 8- and 16-fold higher than those in wild-type mice, respectively. Th e expression level of COX-2 mRNA increased in a time-dependent manner, alth ough COX-1 mRNA was constantly expressed. Treatment with indomethacin, a po tent inhibitor of PG biosynthesis, inhibited UV-induced ear swelling, abrog ated local immunosuppression, and decreased the amount of PGE(2) in the ear skin of XPA-deficient mice, These results indicate that the excess DNA pho toproducts remaining in XPA-deficient cells after UV radiation may induce C OX-2 expression. The induced production of PGE(2) may be involved in the en hanced inflammation and immunosuppression caused by UV radiation in XPA-def icient mice and XP patients.