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Enhanced Photocarcinogenesis in Interleukin-12–Deficient Mice

Departments of ¹ Dermatology and ² Pathology, University Kiel, Kiel, Germany and ³ Department of Dermatology, University Münster, Münster, Germany

Requests for reprints: Thomas Schwarz, Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, D-24105 Kiel, Germany. Phone: 49-431-5971500; Fax: 49-431-5971503; E-mail: tschwarz{at}dermatology.uni-kiel.de.

UV-induced DNA damage is the basis for the development of UV-mediated skin cancer because reduction of DNA damage lowers the risk for photocarcinogenesis. The cytokine interleukin (IL)-12 was shown to exhibit the capacity to reduce UV-induced DNA damage presumably via induction of nucleotide excision repair. Because IL-12 is also produced in the skin, we wondered whether endogenous IL-12 protects from photocarcinogenesis. Therefore, we used knockout mice that lack the IL-12p40 chain and thus do not secrete biologically active IL-12. IL-12p40 knockout (IL-12p40–/–) and wild-type (wt) mice were exposed thrice weekly to UV. Skin biopsies obtained after 6 weeks revealed significantly increased numbers of sunburn cells in IL-12p40–/– mice. Additionally, a higher load of UV-induced pyrimidine dimers could be detected in the skin of UV-exposed IL-12p40–/– mice. Staining of epidermal sheets with an antibody against the tumor suppressor gene p53 revealed a higher number of p53 patches in the skin of IL-12p40–/– mice. After 200 days, first skin tumors developed. Kaplan-Meier analysis indicated a significantly increased probability of tumor development in the IL-12p40–/– mice. In addition, the number of tumors developing in the individual mice was significantly higher in IL-12p40–/– mice than in wt mice. Tumors obtained in IL-12p40–/– mice grew faster than those obtained from wt mice on inoculation into nu/nu mice. This was confirmed in an electrophysiologic assay evaluating the intrinsic invasive potency of tumor cells. Together, these data indicate that IL-12 deficiency is associated with an increased risk to develop UV-induced skin cancer, implying that endogenous IL-12 may protect from photocarcinogenesis. (Cancer Res 2006; 66(6): 2962-9)

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