In mammals, class II cytokines contain interleukins (ILs) and interferons (IFNs), including type I, type II and type III IFNs, which all play important roles in immune system via binding to specific class II cytokine receptors. Fish is reported to possess class II cytokines, including ILs and types I, II and III IFNs, but in teleost fish, the class II cytokine receptor (CRFB) family has seventeen members. 

Other than the classified class II cytokine receptors in teleost fish, there are a few receptors that cannot be classified into orthologues of the known class II cytokine receptors in mammals, such as crfb12. It can be hypothesized that the uncharacterized class II cytokine receptors may interact with unknown cytokine(s) in teleost fish. 

In a recent study published in Nature Communications, the research team led by Prof. NIE Pin from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences revealed another type of IFN, named as type IV, in addition to the currently known three types. 

The researchers first compared zebrafish (Danio rerio) IFN-υ with fish type I IFNs, IL-10 related cytokines and multi-exon type III IFNs in vertebrates. They found that zebrafish (Danio rerio) IFN-υ shares low identity with class II family cytokines and has similar gene organization. Based on antiviral function and receptor usage, IFN-υ was found to have antiviral activity in inducing IFN-stimulated genes (ISGs) expression through class II cytokine receptors, IFN-υR1 (CRFB12) and IL-10R2 (CRFB4). 

The researchers then performed homologous sequence alignments and synteny analyses to determine whether IFNU and IFNUR1 orthologues may exist in other vertebrates. They discovered that IFNU and IFNUR1 are located on conserved loci, and are widely present in lineages of vertebrates, including cartilaginous fishes, teleost fishes, amphibians, reptiles, birds, and mammals, and that vertebrate IFN-υ and IFN-υR1 are clustered together to separately form a unique clade in phylogenetic analysis of class II cytokines and their receptors. 

Besides, the researchers identified ifnu, ifnur1 and il10rb from clawed frog (Xenopus laevis) A6 cell line, and revealed that the clawed frog IFN-υ also has antiviral activity through the receptor subunits, IFN-υR1 and IL-10R2. 

According to the sequence feature, genetic locus, phylogeny and receptor usage, the IFN-υ identified in this study cannot be classified into any of the known IFNs types, but should be considered as the fourth type of IFN. This study contributes to the understanding of IFN systems and their evolution in vertebrates.