Carcinogen-Induced Inflammation and Immunosuppression Are Enhanced in Xeroderma Pigmentosum Group A Model Mice Associated with Hyperproduction of Prostaglandin E2

Abstract

Xeroderma pigmentosum group A (XPA) gene-deficient mice easily developed skin cancers by the application of topical chemical carcinogens as well as by UV irradiation. As certain chemical carcinogens have been shown to be immunosuppressive, we examined the inflammatory and immunosuppressive effects of dimethylbenz(a)anthracene (DMBA) on XPA mice. Compared with wild-type mice, XPA mice showed greater ear swelling and reduction of epidermal Langerhans cells after DMBA application. Topical application of DMBA impaired the induction of contact hypersensitivity, initiated either locally or at distant sites. These DMBA-induced local and systemic immunosuppressions were more greatly enhanced in XPA mice than in wild-type mice. DMBA application induced pronounced production of PGE2, IL-10, and TNF-α in the skin of XPA mice. Treatment with indomethacin, a potent inhibitor of PG biosynthesis, inhibited DMBA-induced inflammation and local immunosuppression. In XPA mice, increased serum IL-10 was detected after DMBA treatment. Excess production of PGE2, TNF-α, and IL-10 after DMBA application may be involved in the enhanced local and systemic immunosuppression in DMBA-treated XPA mice. Susceptibility to DMBA-induced skin tumors in XPA mice may be due to easy impairment of the immune system by DMBA in addition to a defect in the repair of DMBA-DNA adduct. Enhanced immunosuppression by chemical carcinogens as well as the mutagenicity of these mutagens might be associated with the high incidence of internal malignancies seen in XP patients. Moreover, these results supported the hypothesis that persistent DNA damage is a trigger for the production of immunoregulatory cytokines.

XPA Gene-Deficient, SCF-Transgenic Mice with Epidermal Melanin Are Resistant to UV-Induced Carcinogenesis

“…Skin inflammation induced by UVB radiation or DMBA application The ear swelling responses after UVB irradiation or DMBA application in XPA (À/À) mice and XPA (À/À), SCF-Tg mice are shown in Fig 2. XPA (À/À) mice showed marked ear swelling by UVB irradiation at 100 mJ per cm 2 of UVB irradiation as previously reported (Miyauchi-Hashimoto et al, 2001). In contrast, XPA (À/À), SCF-Tg mice did not show any significant swelling at the same dose.…”

Prostaglandin E2 suppresses CCL27 production through EP2 and EP3 receptors in human keratinocytes

“…3 On the other hand, PGE 2 preferentially enhances the production of immunosuppressive type 2 cytokines, such as IL-4 or IL-10, and thus suppresses the induction of delayed-type hypersensitivity in the skin. 4,5 It has been reported that the PGE 2 level is increased in the skin lesions of patients with AD or PV, 6 whereas some studies have reported the decrease of PGE 2 levels in PV lesions. 7 It is thus anticipated that PGE 2 might modulate CCL27 production by keratinocytes in AD or PV lesions.…”

The Photocarcinogenesis of Antibiotic Lomefloxacin and UVA Radiation Is Enhanced in Xeroderma Pigmentosum Group A Gene-Deficient Mice

“…The most possible candidate molecule that initiates UVB-induced immunosuppression is epidermal DNA (Kripke et al, 1992;Vink et al, 1997). We have previously confirmed that UVB-and chemical carcinogen-induced immunosuppression is enhanced in XPA(À/À) mice associated with hyperproduction of immunosuppressive factors such as prostaglandin E2, tumor necrosis factor-a and interleukin-10 (Miyauchi- Hashimoto et al, 1996Hashimoto et al, , 2001Kuwamoto et al, 2000). Consequently, it is also reasonable to speculate that LFLX plus UVA may induce immunosuppression, and accelerate the photocarcinogenesis by similar mechanisms.…”