Ultraviolet Radiation-Induced Impairment of Tumor Rejection Is Enhanced in Xeroderma Pigmentosum A Gene-Deficient Mice

Xeroderma pigmentosum (XP)A gene-deficient mice display dermatologic abnormalities similar to human XP, such as enhanced ultraviolet (UV)-induced acute inflammation and high incidence of UVB-induced skin cancer. We have previously reported that UVB-induced immunosuppression of contact hypersensitivity was greatly enhanced in XPA mice. In the present study, we examined the effects of UVB radiation on tumor rejection in XPA mice. Tumor cells established from UVB-induced squamous cell carcinoma in XPA mice were injected subcutaneously. No difference in the development of tumors was observed between the non-irradiated XPA and wild-type mice. Tumors developed, grew in size, and reached the maximum at 7–10 d after the inoculation. Thereafter, all tumors decreased in size and were completely rejected by 4 wk in both strains of mice. When tumor cells were inoculated into the skin that had been irradiated with 50–150 mJ per cm2 of UVB, tumor grew in 60% (12 of 20) of the XPA mice, but only in 4% (one of 23) of wild-type mice. Phenotyping of tumor-infiltrating cells revealed that the migration of natural killer cells and CD8(+) T cells was inhibited in UVB-irradiated XPA mice. These data suggest that enhanced UVB-induced impairment of tumor rejection could be partially involved in the cancer development of XP patients

Evaluation of Apoptotic Cells Induced by Ultraviolet Light B Radiation in Epidermal Sheets Stained by the TUNEL Technique

Two major components of epidermal cells, keratinocytes and Langerhans cells, are injured by ultraviolet light B radiation, resulting in sunburn cell (apoptotic cell) formation, impaired function, and a reduced number of Langerhans cells. Quantitative analysis of Langerhans cell damage is usually performed using epidermal sheets, whereas that of keratinocytes has been performed by counting the number of sunburn cells in vertical tissue sections. In this study we assessed the influences of ultraviolet light B radiation on epidermal cells by apoptotic cell formation, using murine epidermal sheets stained by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling technique. Ten to 75 mJ per cm2 of ultraviolet light B radiation induced apoptotic cells in abdominal skin of C3H mice. The cells were induced in 6 h after 50 mJ per cm2 of ultraviolet light B irradiation with the peak in number in 24 h, 18.8 ± 5.0 per mm2 and 97.7 ± 7.4 per mm2, respectively. One week later, the apoptotic cells were not visualized. As C3H/He, BALB/C, and C57BL/6 mice showed almost the same frequency of apoptosis in epidermal sheets from 50 mJ per cm2 ultraviolet light B-irradiated skin, the induction of the cells by ultraviolet light B radiation did not depend on the genetic trait of the mouse. Xeroderma pigmentosum type A gene-deficient mice, however, showed a greater induction of apoptotic cells (216.9 ± 25.2 per mm2) by ultraviolet light B radiation than xeroderma pigmentosum type A wild-type mice (89.5 ± 13.6 per mm2) and conventional mice. Pretreatment with a SPF 60 sunscreen agent was quite effective in reducing the induction of apoptotic cells. Using confocal laser scanning microscopy and double staining, 1.5 ± 2.7% of apoptotic cells were Ia-positive cells in 24 h after 50 mJ per cm2 of ultraviolet light B radiation. Apoptotic Ia-positive cells were not observed 48 h after the radiation. On the other hand, no apoptotic dendritic epidermal T cells were observed in up to 75 mJ per cm2 of ultraviolet light B radiated skin. Thus, nearly all apoptotic cells were keratinocytes, and Langerhans cells and dendritic epidermal T cells appeared resistant to ultraviolet light B-induced apoptosis. Compared with the assessment in vertical tissue sections, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling technique with epidermal sheets appeared to be a more physiologically relevant method for quantitative evaluation of apoptotic epidermal cells induced by ultraviolet light B radiation

Photobiologic and Photoimmunologic Characteristics of XPA Gene-Deficient Mice

Xeroderma pigmentosum group A (XPA) gene-deficient mice cannot repair UV-induced DNA damage and easily develop skin cancers by UV irradiation. Just like human XP patients, homozygous (–/–) mice developed stronger longer-lasting acute inflammation than did wild-type mice after a single irradiation with UVB. Moreover, the model mice showed more severe UV-induced damage of keratinocytes and Langerhans cells than did the control mice. UVB-induced local and systemic immunosuppression was greatly enhanced in the (–/–) mice. Treatment with indomethacin, an inhibitor of prostaglandin (PG) synthesis, inhibited UV-induced inflammation and abrogated immunosuppression. In XPA-deficient mice, the amount of PGE2 and the expression level of COX-2 mRNA greatly increased after UVB irradiation compared with wild-type mice. These results suggest that the excess DNA photoproducts remaining in XPA-deficient cells after UV radiation induce COX-2 expression and subsequently produce a high amount of PGE2, which causes the enhancement of inflammation and immunosuppression. In XPA-deficient mice, the natural killer cell activity significantly decreased after repeated exposures to UVB. Our experimental data indicate that cancer development in XP patients involves not only mutagenesis due to the defect in DNA repair, but also the enhanced UV-immunosuppression and intensified impairment of natural killer function

Age Scale for Assessing Activities of Daily Living

The purpose of this study was to develop an age scale for assessing activities of daily living (ADL) among community-dwelling adults aged 75 years or older. Participants were 1006 older Japanese: 312 men (79.6 ± 4.3 years) and 694 women, (79.9 ± 5.5 years). Participants completed a battery of 8 performance tests related to ADL and the Barthel index (BI) questionnaire. Spearman rank-order correlation analysis was applied to obtain the correlation of the 8 ADL performance tests with the total BI score. Three variables were high rank-order correlated with BI, secondly those items were subjected to the principal component analysis. The weighted combination of the principal component scores was summed. Resulting in an ADL score (ADLS), women = 0.075 X1 - 0.082 X2 - 0.063 X3 + 0.124, men = 0.051 X1 - 0.105 X2 - 0.099 X3 + 0.249, where X1 = hand-grip strength, X2 = timed up and go, X3 = five-chair sit to stand. Individual ADLS was transformed to an ADL age scale (ADLA). The estimation was - 5.493 ADLS + 79.90 for women, and - 4.272 ADLS + 79.57 for men. Due to the distortion at the regression edges, the equation was corrected as suggested by Dubina et al. ADLA women after correction was = 0.447 (chronological age: CA) - 5.49ADLS + 44.17, men = 0.519CA - 4.27ADLS + 38.26. ADLA can be used to identify or monitor the characteristics of the ADL levels of physical abilities in older Japanese aged 75 years or older

UV-Induced Ubiquitylation of XPC Protein Mediated by UV-DDB-Ubiquitin Ligase Complex

SummaryThe xeroderma pigmentosum group C (XPC) protein complex plays a key role in recognizing DNA damage throughout the genome for mammalian nucleotide excision repair (NER). Ultraviolet light (UV)-damaged DNA binding protein (UV-DDB) is another complex that appears to be involved in the recognition of NER-inducing damage, although the precise role it plays and its relationship to XPC remain to be elucidated. Here we show that XPC undergoes reversible ubiquitylation upon UV irradiation of cells and that this depends on the presence of functional UV-DDB activity. XPC and UV-DDB were demonstrated to interact physically, and both are polyubiquitylated by the recombinant UV-DDB-ubiquitin ligase complex. The polyubiquitylation altered the DNA binding properties of XPC and UV-DDB and appeared to be required for cell-free NER of UV-induced (6-4) photoproducts specifically when UV-DDB was bound to the lesion. Our results strongly suggest that ubiquitylation plays a critical role in the transfer of the UV-induced lesion from UV-DDB to XPC