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. 2010 Feb;3(2):179-89.
doi: 10.1158/1940-6207.CAPR-09-0044. Epub 2010 Jan 26.

Green tea polyphenols prevent UV-induced immunosuppression by rapid repair of DNA damage and enhancement of nucleotide excision repair genes

Santosh K Katiyar  1 , Mudit Vaid, Harry van Steeg, Syed M Meeran
Affiliations

Green tea polyphenols prevent UV-induced immunosuppression by rapid repair of DNA damage and enhancement of nucleotide excision repair genes

Santosh K Katiyar et al. Cancer Prev Res (Phila). 2010 Feb.

Abstract

UV radiation-induced immunosuppression has been implicated in the development of skin cancers. Green tea polyphenols (GTP) in drinking water prevent photocarcinogenesis in the skin of mice. We studied whether GTPs in drinking water (0.1-0.5%, w/v) prevent UV-induced immunosuppression and (if so) potential mechanisms of this effect in mice. GTPs (0.2% and 0.5%, w/v) reduced UV-induced suppression of contact hypersensitivity (CHS) in response to a contact sensitizer in local (58-62% reductions; P < 0.001) and systemic (51-55% reductions; P < 0.005) models of CHS. Compared with untreated mice, GTP-treated mice (0.2%, w/v) had a reduced number of cyclobutane pyrimidine dimer-positive (CPD(+)) cells (59%; P < 0.001) in the skin, showing faster repair of UV-induced DNA damage, and had a reduced (2-fold) migration of CPD(+) cells from the skin to draining lymph nodes, which was associated with elevated levels of nucleotide excision repair (NER) genes. GTPs did not prevent UV-induced immunosuppression in NER-deficient mice but significantly prevented it in NER-proficient mice (P < 0.001); immunohistochemical analysis of CPD(+) cells indicated that GTPs reduced the numbers of UV-induced CPD(+) cells in NER-proficient mice (P < 0.001) but not in NER-deficient mice. Southwestern dot-blot analysis revealed that GTPs repaired UV-induced CPDs in xeroderma pigmentosum complementation group A (XPA)-proficient cells of a healthy person but did not in XPA-deficient cells obtained from XPA patients, indicating that a NER mechanism is involved in DNA repair. This study is the first to show a novel NER mechanism by which drinking GTPs prevents UV-induced immunosuppression and that inhibiting UV-induced immunosuppression may underlie the chemopreventive activity of GTPs against photocarcinogenesis.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest: No conflict of interest.

Figures

Figure 1
Figure 1
Drinking GTPs inhibit UVB-induced suppression of the CHS response in local as well as systemic model of CHS in C3H/HeN mice. A, The UVB-irradiated mice that did not receive treatment with GTPs did not exhibit a significant response on DNFB challenge when sensitized through the UVB-irradiated skin (local immunosuppression). Mice that were treated with GTPs in drinking water before and during CHS protocol induce a CHS response in a dose-dependent manner (0.1, 0.2 or 0.5%, w/v). Mice were rested for 4 weeks after primary challenge and further challenged with DNFB (Secondary challenge). The change in ear skin thickness in each group was measured, as shown in right hand Panel of Panel A. B, GTPs inhibit UVB-induced suppression of CHS response in systemic model of CHS in C3H/HeN mice. The UVB-irradiated mice that did not receive treatment with GTPs did not exhibit a significant response on DNFB challenge when sensitized through the non-UVB-irradiated distant abdominal skin site (systemic immunosuppression). Mice that were treated with GTPs before and during CHS protocol were able to induce a CHS response preferably at the doses of 0.2 and 0.5% of GTPs in drinking water. GTPs do not affect the ability of the mice to generate CHS response to DNFB (Panels A & B, 3rd-5th bars from the top). The change in ear swelling response in each group is reported as mean ± SD, n=5 per group. Each experiment was repeated twice with similar observations. *Significant versus non-GTPs (UVB alone) treated animals, p<0.001 Significant versus non-GTPs treated and UVB-exposed animals, p<0.005
Figure 2
Figure 2
GTPs repair or remove UV-induced CPDs more rapidly in mice than those mice which were not given GTPs in water. Panel A, Mice were exposed to UV (60 mJ/cm2) radiation with or without the treatment of GTPs in drinking water. Mice were sacrificed at 30 min (immediate) or 72 hour later and skin samples collected and frozen in OCT medium. Frozen sections (5 μm thick) were subjected to immunoperoxidase staining to detect CPD+ cells. CPD+ cells are shown in dark brown. CPD+ cells were not detected in non-UVB exposed skin. Magnification= 40×. Panel B, The numbers of CPD+ cells were counted in 5-6 different areas of the sections under microscope and the numbers reported represent the percentage of CPD+ cells ± SD in epidermis, n=5. *Significant difference versus UV alone, p<0.001. ND = not detectable.
Figure 3
Figure 3
Administration of GTPs in drinking water reduces the migration of CPD+ cells from the skin to draining lymph nodes of UV-exposed mice compared to the lymph nodes of non-GTPs-treated UVB-exposed mice. Panel A, Mice were treated with GTPs then exposed to UV (60 mJ/cm2), as detailed in Materials and methods. Mice were sacrificed 36 hours later and the DLN harvested and frozen in OCT. DLN obtained from non-UV-exposed mice were used as controls. CPD+ cells were detected by immunoperoxidase staining of frozen sections as described in Materials and methods. CPD+ cells were not detectable in DLN obtained from non-UV exposed control mice. Five mice were used per group and the experiment was repeated once. Magnification= 20×. Panel B, The numbers of CPD+ cells were counted in 5 to 6 different areas of the sections and the numbers reported represent the number of CPD+ cells per microscopic field as a mean ± SD in the draining lymph nodes. n=5. ND= not detectable in non-UV-exposed mice. *Significant difference versus UVB alone, p<0.001.
Figure 4
Figure 4
Administration of GTPs enhances the levels of mRNA expression of NER genes in the UVB-exposed mouse skin than non-GTPs-treated UVB-irradiated mouse skin. Mice were exposed to UVB (90 mJ/cm2) with or without the treatment of GTPs, then sacrificed at 1 and 3 hours later. The levels of mRNA expression were determined using real-time PCR. The data of mRNA expression levels of various NER genes are expressed as mean ± SD. Five mice were used per group and the experiment was repeated once. Statistically significant versus UVB alone, *p<0.001, †p<0.05.
Figure 5
Figure 5
Administration of GTPs in drinking water does not prevent UVB-induced suppression of the CHS response in XPA-/- mice but prevent in wild-type counterparts. The shaved backs of mice were exposed to UVB radiation (100 mJ/cm2) with or without the prior treatment of GTPs in drinking water (0.2%, w/v) on four consecutive days. Twenty-four hours after the last UVB exposure, the mice were sensitized with DNFB through UVB-exposed dorsal skin. Five days after sensitization, the mice were challenged by painting DNFB on the ear, and ear swelling was measured, as detailed in Materials and methods. The change in ear thickness is reported in millimeter (mm ×10-2) as the mean ± SD, n=5 per group. The experiment was repeated twice with similar results. †Significant inhibition versus positive control, p<0.001. *Significant sensitization versus non-GTPs-treated (UVB alone) wild-type mice; p<0.005.
Figure 6
Figure 6
GTPs reduce or repair UVB-induced DNA damage in XPA-proficient (wild-types) mice but do not reduce or repair UVB-induced DNA damage in XPA-deficient mice. Panel A, Shaved dorsal skin of the mice were exposed to UVB (50 mJ/cm2) with or without the treatment of GTPs in drinking water, as detailed in Materials and methods. Mice were sacrificed 48 hours after UV irradiation, skin samples were collected and frozen in OCT medium for immunoperoxidase staining of CPD-positive cells, as described in Materials and methods. CPD+ cells are shown as dark brown. Magnification= 40×. Panel B, The numbers of CPD+ cells were counted in 5 to 6 areas of the section and are expressed in terms of the percentage of CPD+ cells as a mean ± SD. n=5. *Significant decrease versus non-GTPs-treated but UVB-irradiated wild-type (XPA+/+) mice, p<0.001. Panel C, Treatment of GTPs enhances the repair of UVB-induced DNA damage in XPA-proficient human fibroblast cells but does not repair UVB-induced DNA damage in XPA-deficient cells. XPA-proficient cells from a healthy person and XPA-deficient cells from a patient suffering from xeroderma pigmentosum with a deficiency in XP complementation group A were exposed to UV (20 mJ/cm2) in the presence or absence of GTPs (20 μg/ml) and cells were harvested 36 hours later. Genomic DNA was extracted from cells treated as described above and subjected to Southwestern dot-blot analysis using an antibody against CPD. The cells which were not exposed to UVB did not show the presence of CPDs in the dot-blot. Experiments were repeated twice with identical observations.
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