Enhanced photocarcinogenesis in interleukin-12-deficient mice.
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 approximately 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.
Maeda
Akira
A
Department of Dermatology, University Kiel, Kiel, Germany.
Schneider
Stefan W
SW
Kojima
Motohiro
M
Beissert
Stefan
S
Schwarz
Thomas
T
Schwarz
Agatha
A
D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics / Q000528:radiation effects; D003043:Cocarcinogenesis; D017097:Electric Impedance; D016158:Genes, p53 / Q000235:genetics / Q000528:radiation effects; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics; D011740:Pyrimidine Dimers / Q000378:metabolism / Q000528:radiation effects; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D013471:Sunburn / Q000473:pathology; D014466:Ultraviolet Rays
D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D011740:Pyrimidine Dimers; D016753:Interleukin-10; D018664:Interleukin-12