Transgenic expression of S100A2 in hairless mouse skin enhances Cxcl13 mRNA in response to solar-simulated radiation.
S100A2 is a homodimeric protein that undergoes oxidative cross-linking and translocation from the nucleus to the cytosol in the context of oxidative stress. Suggestive of a role for S100A2 in the cutaneous response to ultraviolet light, we found altered S100A2 immunostaining in photodamaged human skin, and crosslinking of S100A2 after ultraviolet A (UVA) irradiation of normal human keratinocytes (NHK). Skin from mice, rats, and rabbits did not contain S100A2 protein, whereas skin samples from pigs, frogs and humans were strongly positive. Survival after UVA irradiation was significantly greater in NHK compared to mouse keratinocytes, suggesting a protective role for S100A2. To test this hypothesis in vivo, we expressed S100A2 in SKH2/J hairless mice under the control of a bovine keratin 5 promoter, and compared responses of TG and WT mice from 1 to 7 days after a single dose (0.5-1 MED) of solar-simulated radiation (SSR) from UVA-340 bulbs. WT and TG mice manifested a similarly robust response to SSR, characterized by epidermal hyperplasia, marked induction of p21(WAF), and a twofold increase in p53. Thymine dimers (TD) were markedly increased in the epidermis and the dermis, but while over 95% of the epidermal TD were removed by 5-6 days, elevated dermal TD persisted nearly unchanged for 7 days. Global transcriptional profiling of WT and TG mice revealed strong induction of multiple transcripts, including keratins K6 and K16, defensin beta 3, S100A8, S100A9, Sprr2i and Sprr2f. However, the only S100A2-dependent difference we observed was an induction of Cxcl13 transcripts in TG, but not WT mice (4.4-fold vs. 0.7-fold, n = 3, P = 0.022). This finding was confirmed in an independent set of mice analyzed by quantitative RT-PCR (8.8-fold vs. 1.2-fold, n = 4, P = 0.001). The finding of persistent dermal DNA damage after suberythemal doses of SSR merits further study.
Li
Yong
Y
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-0932, USA.
Gudjonsson
Johann E
JE
Woods
Timothy L
TL
Zhang
Tong
T
Johnston
Andrew
A
Stoll
Stefan W
SW
Elder
James T
JT
D000818:Animals; D002478:Cells, Cultured; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism*; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D023421:Models, Animal; D011565:Psoriasis / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D002630:Chemotactic Factors; C486386:Cxcl13 protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D009418:S100 Proteins; C098997:S100A2 protein, human; C539698:S100A2 protein, mouse; D016159:Tumor Suppressor Protein p53