IFN-alpha subtypes are well described (5-9). There are 15 human IFN-alpha subtypes with 80% amino acid
identity (10). The number of IFN-alpha subtypes varies by species with 6 equine subtypes, 17 porcine
subtypes, 14 bovine subtypes, and 9 canine subtypes known currently. Human IFN-alpha subtypes
include: IFN-alpha 1a, IFN-alpha 1b, IFN-alpha 2a, IFN-alpha 2b, IFN-alpha 4a, IFN-alpha 4b, IFN-alpha 5, IFN-alpha 6 IFN-alpha 7, IFN-alpha 8,
IFN-alpha 10, IFN-alpha 14, IFN-alpha 16, IFN-alpha 17, and IFN-alpha 21. Although there is one known heterodimeric IFN-alpha
receptor (IFN-alpha R, described below), each IFN-alpha subtype has been correlated with differing biological
activities (7). Variability in biological responses can be attributed to differences in binding affinity
and duration, receptor density, feedback responses and intracellular characteristics (11). IFN-alpha
responses have been described as robust, especially in the context of viral infection responsiveness
by all cells or tunable in a cell type specific manner.
IFN-alpha signaling is well characterized (2, 5,11,12,13). IFN-alpha is a ligand for IFN alpha R, which includes two
subunits IFN alpha R1 and IFN alpha R2. IFN-alpha ligand binding to the ubiquitously expressed IFN alpha R1 triggers
a conformational change which allows for the heterodimerization of IFN alpha R1 and IFN alpha R2 (10).
Heterodimerization results in the cross phosphorylation of the Janus-activated Kinase 1 (JAK1)
on IFN alpha R2 and tyrosine kinase 2 (TYK2) on IFN alpha R1 respectively, as well as the intracellular domain
of IFN alpha R1 and IFN alpha 2 (9). The transcription factors Signal transducer and activator of transcription
(STAT) 1 and 2 are subsequently recruited to IFN alpha R via their Src homology 2 (SH2) domain and
phosphorylated. In the canonical IFN-alpha signaling pathway, phosphoSTAT1/STAT2 heterodimers
associate with Interferon Regulatory Factor 9 (IRF9) to form Interferon Stimulated Gene
Factor 3 (ISGF3), which translocates into the nucleus to bind to gamma-activated sequences (GASs)
or interferon- stimulated response elements (ISREs). This stimulates the transcription of interferonstimulated genes (ISGs). STAT 2 homodimers and monomers can also associate with IRF-9 to form
ISGF3-like complex, which also binds to ISRE to stimulate the transcription of ISGs (9).
Although IFN-alpha is most commonly associated with viral infections, it has been associated with
other pathological events. Type 1 interferons represent a standard of care for suppressing Hepatitis
B (HBV) or C (HCV) (14). However, it has been associated with neuropsychiatric symptoms such
as depression, anhedonia, anxiety and cognitive impairment (15). The role of IFN-alpha in cancer is
complex as well. For example, in the context of inflammatory breast cancer, IFN-alpha is upregulated.
Although IFN-alpha has been correlated with cellular senescence and apoptosis, some subtypes have
been correlated with increased cellular migration and drug resistance.
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