Carcinogen-induced inflammation and immunosuppression are enhanced in xeroderma pigmentosum group A model mice associated with hyperproduction of prostaglandin E-2

Xeroderma pigmentosum group A (XPA) gene-deficient mice easily developed sk in cancers by the application of topical chemical carcinogens as well as by UV irradiation. As certain chemical carcinogens have been shown to be immu nosuppressive, we examined the inflammatory and immunosuppressive effects o f dimethylbenz(a)anthracene (DMBA) on XPA mice. Compared with wild-type mic e, XPA mice showed greater ear swelling and reduction of epidermal Langerha ns cells after DMBA application. Topical application of DMBA impaired the i nduction of contact hypersensitivity, initiated either locally or at distan t sites. These DMBA-induced local and systemic immunosuppressions were more greatly enhanced in XPA mice than in wild-type mice. DMBA application indu ced pronounced production of PGE(2), IL-10, and TNF-alpha in the skin of XP A mice. Treatment with indomethacin, a potent inhibitor of PG biosynthesis, inhibited DMBA-induced inflammation and local immunosuppression. In XPA mi ce, increased serum IL-10 was detected after DMBA treatment. Excess product ion of PGE(2), TNF-alpha, and IL-10 after DMBA application may be involved in the enhanced local and systemic immunosuppression in DMBA-treated XPA mi ce. Susceptibility to DMBA-induced skin tumors in XPA mice may be due to ea sy impairment of the immune system by DMBA in addition to a defect in the r epair of DMBA-DNA adduct. Enhanced immunosuppression by chemical carcinogen s as well as the mutagenicity of these mutagens might be associated with th e high incidence of internal malignancies seen in XP patients. Moreover, th ese results supported the hypothesis that persistent DNA damage is a trigge r for the production of immunoregulatory cytokines.