Regulation of ultraviolet radiation-induced cutaneous DNA damage by type I interferons

Abstract

Abstract Type I interferons (IFNs) are cytokines, that are important regulators of immune responses and are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) radiation is a proven environmental carcinogen, and exposure to solar radiation contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in repair and replication of DNA. It is believed that type I IFNs reduce cellular proliferation and allow DNA repair in various diseases. Interferon receptor 1 (IFNAR1) is critical for signaling of type I IFNs. We hypothesized that type I IFNs (IFNα/β) will repair UVB induced DNA damage in mice. To test our hypothesis, shaved mice lacking IFNAR1 and wild type mice on a C57BL/6 background were irradiated with single dose of UVB radiation (100 mJ/cm2). Skin samples were examined for CPD by immunofluorescence and ELISA. We found that mice lacking IFNAR1 had more CPD as evident by ELISA and histology. In order to determine the cell type, which produces type I IFNs in skin after UVB exposure, single cell suspensions were prepared from irradiated skin samples and stained for type I IFNs using flow cytometry. We found that type I IFNs were produced by inflammatory monocytes (CD45+CD11b+Ly6C+). We also found that DNA repair gene XPA was downregulated in the mice lacking IFNAR1. In conclusion, our studies show that mice lacking the IFNAR1 had decreased repair of UVB induced CPD in the skin. Our ongoing studies will elucidate whether type I IFNs regulate development of UVB induced skin tumors.