Abstract
Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure 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 the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNβ in the skin of C57BL/6 mice. IFNα and IFNβ were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.
Highlights
Introduction iationsUltraviolet (UV) B radiation (290–320 nm) is an important trigger for the suppression of immune responses and the initiation of non-melanoma skin cancers [1,2,3]
Mice were sacrificed at various time intervals (30 m, 24 h, and 48 h) and their skin was analyzed for IFNα and IFNβ, IRF1, IRF3, and IRF7 using a quantitative real-time PCR
We investigated whether the decreased DNA repair in the absence of IFNAR1 was due to the attenuated stimulation of nucleotide excision repair (NER) that can be assayed by measurement of xeroderma pigmentosum A (XPA) expression [4]
Summary
Ultraviolet (UV) B radiation (290–320 nm) is an important trigger for the suppression of immune responses and the initiation of non-melanoma skin cancers [1,2,3]. The molecular basis for these biological activities stems at least in part from its ability to damage DNA, predominantly in the form of cyclobutane pyrimidine dimers (CPD). DNA damage occurs in cells, there is a meticulous attempt to repair it through the activation of DNA repair enzymes [4]. Xeroderma pigmentosum (XP), an autosomal recessive disorder of DNA repair, is associated with a greater than 1000-fold increase in the susceptibility to UVB-induced skin malignancies. UVB-induced DNA damage is of importance in skin cancer and plays a critical role in UVB-induced immune suppression [5].
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