Interferons (IFNs) are a family of naturally existing glycoproteins known for their antiviral activity and their ability to influence the behavior of normal and transformed cell types. Type I Interferons include IFN-α and IFN-β. Currently, IFN-α has numerous approved antitumor applications, including malignant melanoma, in which IFN-α has been shown to increase relapse free survival. Moreover, IFN-α has been successfully used in the intralesional treatment of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In spite of these promising clinical results; however, there exists a paucity of knowledge on the precise anti-tumor action of IFN-α/β at the cellular and molecular levels in cutaneous malignancies such as SCC, BCC, and melanoma. This review summarizes current knowledge on the extent to which Type I IFN influences proliferation, apoptosis, angiogenesis, and immune function in normal skin, cutaneous SCC, BCC, and melanoma. 1. Introduction Interferons (IFNs) are a group of naturally existing glycoproteins that are secreted by cells in response to viral infections as well as synthetic and biologic inducers. Since the discovery of IFNs more than 50 years ago, in vitro and in vivo assays have demonstrated a diverse spectrum of biological activity, including antiviral, antiproliferative, and immunomodulatory properties [1]. Type I interferons include IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω. Type II interferons include IFN-γ, and type III interferons include IFN-λ [1–3]. Type I interferons (IFN-α, IFN-β) bind to cell surface receptors with two distinct subunits: IFN-α receptor 1 and IFN-α receptor 2. This binding triggers phosphorylation of janus kinase 1 (JAK1) and tyrosine kinase 2 (TK2), members of the Janus kinase family of receptor-associated tyrosine kinases. These kinases proceed to phosphorylate signal transducers and activators of transcriptions 1 and 2 (STAT1 and STAT2), which belong to a group of latent cytoplasmic transcription factors. The activated STAT1 and STAT2 proteins complex with p48 protein to form the IFN-stimulated gene factor 3 (ISGF3) transcription factor. ISGF3 translocates to the nucleus, where it binds to IFN-stimulated response elements in the promoters of type I IFN-responsive genes and thereby activates transcription [4, 5]. IFN-γ signals through the cell surface receptor IFNGR, which consists of IFNGR1 and IFNGR2 chains, impacting distinct but related pathways to those of type I IFN. IFN-λ signals through the unique receptors IFNLR1 and IFN-10R2 [3]. Among the interferons, IFN-α2 has been the most broadly
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