Solar ultraviolet irradiation activates IFNy/STAT1 signaling pathway in the epidermis
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Signal transducer and activator of transcription 1 (STAT1) is a latent transcription factor activated by Interferon-γ (IFNγ) receptor. The role of STAT1 in epithelial carcinogenesis remains poorly defined. Previous work performed in our lab showed that STAT1 was absolutely required for skin cancer promotion by chrysarobin using the multistage skin carcinogenesis model. A novel mechanism of skin tumor promotion involving IFNγ/STAT1 signaling was defined. Interestingly, Solar ultraviolet (SUV) radiation activated IFNγ/STAT1 pathway in a similar pattern as seen with chrysarobin. SUV treatment led to rapid phosphorylation of STAT1 on both tyrosine (Y701) and serine (S727) residues in epidermis. An increase of unphosphorylated STAT1 (uSTAT1) and interferon regulatory factor 1 (IRF1) were also observed and verified to be dependent on STAT1 activation. Further analyses demonstrated that the induction of phosphorylation of STAT1, and the increase of both IRF1 and uSTAT1 was dependent on intact IFNγ signaling. Quantitative PCR detected an increase of STAT1, IRF1 and other downstream targets of IFNγ/STAT1 axis including Cxcl9, Cxcl10, Cxcl11, PD-L1 and Cox2, which all depended on STAT1 activation. IFNγ receptor knockout mice displayed no activation of the IFNγ/STAT1 signaling pathway, weak activation of MAPK signaling and reduced myeloid cells influx into the dermis following exposure to SUV. CD3+ cells were determined to be the only source of IFNγ production in the epidermis following SUV treatment. Also, CD3+ cells were the primary cellular source of IFNγ production after CHRY treatment. A topical ointment application containing an oligonucleotide decoy was formulated to inhibit the activation of IFNγ signaling in the epidermis. Collectively, these findings clearly demonstrate that SUV activates the IFNγ/STAT1 signaling pathway in the mouse epidermis.