Abstract
Type I interferons (IFN-I) were first discovered as an antiviral factor by Isaacs and Lindenmann in 1957, but they are now known to also modulate innate and adaptive immunity and suppress proliferation of cancer cells. While much has been revealed about IFN-I, it remains a mystery as to why there are 16 different IFN-I gene products, including IFNβ, IFNω, and 12 subtypes of IFNα. Here, we discuss shared and unique aspects of these IFN-I in the context of their evolution, expression patterns, and signaling through their shared heterodimeric receptor. We propose that rather than investigating responses to individual IFN-I, these contexts can serve as an alternative approach toward investigating roles for IFNα subtypes. Finally, we review uses of IFNα and IFNβ as therapeutic agents to suppress chronic viral infections or to treat multiple sclerosis.
Highlights
Type I interferons (IFN-I) are monomeric cytokines that are best known for their antiviral activity but that suppress proliferation of cancer cells and modulate innate and adaptive immune responses
IFNk is primarily expressed by keratinocytes [5] where it has recently been shown to have a role in protection against cutaneous herpes simplex virus [6], papilloma virus [7], and cutaneous lupus erythematosus [8]
AExpression patterns determined by mass spectrometry. bExpression patterns determined by RNAseq, which may be insensitive to detecting highly identical transcripts. cLower case “x” refers to the IFNa subtypes that were not expressed after IFNAR2 blockade
Summary
Type I interferons (IFN-I) are monomeric cytokines that are best known for their antiviral activity but that suppress proliferation of cancer cells and modulate innate and adaptive immune responses. We know that human type I IFNs comprise a family of 17 functional genes and 9 pseudogenes clustered on chromosome 9 [3] that encode 16 proteins: IFNb, ε, -k, -w, and 12 subtypes of IFNa (Figure 1). Differences in gene expression, antiviral, or antiproliferative activity at subsaturation are equalized by dose adjustments or in the extreme, by receptor saturation While their evolutionary history and expression patterns suggest that at least some IFN-I serve specific functions, very few have been defined. The critical importance of IRF3 toward initiating IFN expression is emphasized by the number of pathogens with gene products that antagonize its activation [41] and by reports that cells from IRF3-deficient patients express little or no IFNb [42, 43].
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