Inverse relationship between increased apoptosis and decreased skin cancer in UV-irradiated CD1d-/- mice.
We previously demonstrated that CD1d knockout mice were resistant to ultraviolet (UV)-induced immunosuppression. Because immune suppression is a critical factor in the development of UV-induced skin cancers, we investigated the response of wild type (WT) and CD1d-/- mice to UV carcinogenesis. We found that although 100% of WT mice developed skin tumors after 45 weeks of UV irradiation, only 60% of CD1d-/- mice developed skin tumors. To investigate the mechanisms involved in the resistance of CD1d-/- mice to UV-induced carcinogenesis, we determined the time course and kinetics of keratinocyte cell death after UV irradiation. After acute UV exposure, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL)-positive keratinocytes were eliminated from the skin of WT mice by 72 h post-UV, but they still persisted until 96 h in CD1d-/- mice. The kinetics of p53 protein expression closely followed the kinetics of apoptotic cell death. Chronic UV irradiation resulted in induction of a significantly higher number of apoptotic keratinocytes in CD1d-/- than WT mice. In addition, epidermis and dermis from chronically UV-irradiated CD1d-/- mice harbored significantly fewer p53 mutations than WT mice. These results indicate that the resistance of CD1d-/- mice to UV carcinogenesis may be due to increased cell death and elimination of keratinocytes and fibroblasts containing DNA damage and p53 mutations.
Matsumura
Yasuhiro
Y
Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. matsumy@takii.kmu.ac.jp
Moodycliffe
Angus M
AM
Nghiem
Dat X
DX
Ullrich
Stephen E
SE
Ananthaswamy
Honnavara N
HN
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000502:physiology*; D055610:Antigens, CD1d; D017209:Apoptosis; D016158:Genes, p53; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D014466:Ultraviolet Rays
D018949:Antigens, CD1; D055610:Antigens, CD1d