Chronic exposure to solar UV radiation is the major etiological agent for over one million new non-melanoma skin cancers in the United States each year and is an important factor in the pathogenesis of melanoma, premature aging of the skin and immunosuppression. Non-melanoma skin cancer is by far the most common cutaneous malignancy and has a tremendous impact on public health and health care expenditures. There has been a concerted effort to identify complementary and alternative medicine that will protect against the adverse biological effects of UV radiation overexposure. A polyphenolic fraction isolated from green tea (GTP) has remarkable chemopreventive effects against photocarcinogenesis and UV-induced immunosuppression. The proposed studies in this proposal are based on our observations that, in mice, administration of GTP either topically or in drinking water (d.w.) inhibits UVB-induced suppression of immune responses and this inhibition was associated with the synergistic effect on IL-12 production with UV radiation. As IL-12 is known to reverse UV-induced immunosuppression, which is considered to be a risk factor for cancer induction, and has anti-tumor activity, we postulate that GTP mediates its chemopreventive effects, at least in part, through the augmentation of UV-induced IL-12 in mice. We propose the following specific aims to test the hypothesis that GTP given in d.w. to mice modulates UVB-induced immunological responses and subsequently inhibits photocarcinogenesis, at least in part, through its ability to induce IL-12. To test this hypothesis the following Specific Aims are proposed in a mouse model of IL-12 knockouts and their wild type counterparts. We will determine whether IL-12 is involved in the chemopreventive effects of GTP on UVB-induced: (1) photocarcinogenesis, and (2) immunosuppression. These studies also will address whether GTP is equally effective against all types of skin tumors. As UV-induced DNA damage, predominantly in the form of cyclobutane pyrimidine dimers, is an important molecular trigger of UV-induced immunosuppression and initiation of photocarcinogenesis, in Specific Aim-3, we will determine whether GTP treatment reduces UV-induced DNA damage through activation of DNA repair enzymes and if IL-12 is involved in this process. The results obtained from this study may lead to the generation of new knowledge to identify the mechanism of action by which green tea polyphenols exert their skin cancer chemopreventive effects. This will lead to the development of new methods and immunomodulatory strategies for the prevention of solar UV radiation-induced skin cancer in humans by employing polyphenols from green tea as a complementary and alternative medicine. Importantly, worldwide interest in green tea as a cancer chemopreventive agent for humans is increasing because it is non-toxic, affordable, popular beverage and is effective in a wide range of organs. ? ? ?
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