IFNs_at_age_50_past_current_and_future_impact_on_biomedicine

IFNs_at_age_50_past_current_and_future_impact_on_biomedicine...

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The discovery and molecular understanding of the cell- ular mechanisms and clinical use of interferons (IFNs) have been a major advance in biomedicine over the past 50 years. This family of secreted autocrine and para- crine proteins stimulates intracellular and intercellular networks that regulate resistance to viral infections, enhance innate and acquired immune responses, and modulate normal and tumour cell survival and death. After their discovery in 1957 (REF. 1) , it was soon appre- ciated that IFNs were critically important to the health of animals and humans and that the IFN system had potential as therapies for infections for both RNA and DNA viruses (TIMELINE) . However, advances in molecular biology a decade later and into the 1970s were required before the promise could be realized. The 1980s saw their introduction into the clinic as the first pharmaceutical products of the budding biotechnology industry, and, importantly, as a demonstration of the effectiveness of IFNs not only for viral diseases and cancer but also for multiple sclerosis (MS). The 1990s were marked by an expansion in their clinical applications with regulatory approvals world- wide and a further understanding of molecular events influencing biological actions. Current studies have led to new insights into IFNs as a fundamental component of the innate immune system. Additionally, studies have revealed how IFN production is induced through Toll- like receptors (TLRs), the actions of IFN-stimulated genes (ISGs), the identification of viral mechanisms that resist actions of this potent protein, and how mutation and suppression of gene products of the IFN system in and by malignant cells may affect the initiation and progression of cancer. After binding to high-affinity receptors, IFNs initiate a signalling cascade through signalling proteins that can also be activated by other cytokines, which were first identified through studies of IFNs. Cellular actions are mediated through specific ISGs, which underlie the antiviral effects, as well as immunoregu- latory and antitumour effects. Future drugs that could act as molecular activators for ISGs, many of which exist in a latent state or as agonists for TLRs, might be expected to have potent antiviral, antitumour and/or immunomodulatory effects. From more than 100,000 published papers, we offer a perspective with a focus on human IFNs to stimulate the future investigation of important questions. Although IFNs function as an integrated system, conceptually it helps to consider their production, which is medi- ated through TLR activation, and their action, which is mediated through JAK/STAT (Janus kinase/Signal Transducers and Activators of Transcription) and other signalling pathways. The production of IFNs is important for understanding the role of IFNs in innate immunity, while their effects relate to dissecting under- lying and future mechanisms of action and application.
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IFNs_at_age_50_past_current_and_future_impact_on_biomedicine...

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