Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression

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.

Novel Expression of Thymine Dimers in Renal Cell Carcinoma, Demonstrated through Immunohistochemistry

“…These therapeutic results derive from IFN1α’s anti-proliferative and anti-angiogenic effects within RCC tissue, as well as its modulatory cellular differentiation activity via growth factor cross-talk and transcriptional control over key cellular differentiation genes [ 59 , 60 ]. Interestingly, in a very recent murine model investigation, IFN 1α/β demonstrated a novel genomic photo-damage repair activity via NER gene induction and a protective effect against UVR-induced immuno-suppression [ 61 ]. Taking into account the findings of our current study, it may be the case that TDs have constituted an occult molecular therapeutic target in metastatic RCCs undergoing immunomodulatory cytokine treatment via IFN 1α-induced improvements in NER capabilities in TD-positive renal/RCC tissue.…”

Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity

“…First, the rate of skin cancer in autoimmune photosensitive diseases is not comparable to those with DNA repair deficiencies, indicating no persistence of increased nuclear DNA damage( 58 ). Second, type I IFN may increase repair of cyclobutane pyrimidine dimers, the main nuclear DNA lesion upon UV light exposure( 59 ). Third, mtDNA is more susceptible to oxidative modifications due to close proximity to ROS production, a lack of protective histones and insufficient DNA repair mechanisms compared to nuclear DNA( 19, 22, 60 ).…”

Immunotherapy Applications for Thymine Dimers and WT1 Antigen in Renal Cancers: A Comparative Statistical Analysis

“…Furthermore, molecules with antioxidant and inhibitory properties against TD formation, such as α-tocopherol (vitamin E) [ 73 ], isoflavone genistein [ 74 ], and resveratrol [ 75 ], may have potential applications in RCC prevention. Interestingly, a recent study using a murine model revealed IFN 1α/β to have a protective effect against UV-induced immunosuppression, and to enhance genomic photo-damage repair activity via NER gene induction [ 76 ]. Considering the current findings, TDs might have been overlooked as molecular therapeutic targets in metastatic RCCs treated with IFN 1α, by improving NER capabilities in TD-positive renal/RCC tissue.…”