Interferon-λ Is Functionally an Interferon but Structurally Related to the Interleukin-10 Family

Abstract

Interferon-(IFN-) is an antiviral cytokine that signals through a distinct receptor complex, composed of the IFN-R1and interleukin-10R2 (IL-10R2) receptor chains. We have determined the crystal structure of human IFN-3 and characterized the interaction with its receptor complex through structurebased site-directed mutagenesis. The ability of IFN-3 mutants to signal was determined by measuring the antiviral activity and induced STAT2 phosphorylation. In conclusion, our data show that, although IFN-is functionally an interferon, it is clearly structurally related to members of the IL-10 family. In particular, we found an interesting similarity between IFN-and IL-22, and we suggest that IFN-and IL-22 possess parallel functions, protecting epithelial tissue against viral and bacterial infections, respectively.In 2003, a novel family of cytokines was discovered simultaneously by two independent research teams (1, 2). Initially, the two research teams named these novel cytokines either interferon-(IFN-) 2 1, 2, and 3 or interleukin-29 (IL-29), -28A, or -28B. Throughout this report we will use the IFN-designation or type III IFN, when referring to all tree subtypes as a group. Like type I IFN, type III IFN induces antiviral activity both in vitro (3, 4) and in vivo (5). Thus the two types of IFN seem to have similar biological effects at a cellular level. IFN-uses a distinct receptor complex consisting of a unique subunit, named IFN-R1, as well as the IL-10R2 subunit. The similar biological effects caused by type I and III IFN can be explained by activation of a highly overlapping set of transcription factors. In particular, both types of IFN lead to phosphorylation of signal transducers and activators of transcription (STAT) 1, 2, and 3, followed by assembly of the interferon-stimulated gene factor 3 transcription factor and thus target the same population of genes for induction (6 -8).The expression of type III IFN appears to be induced by the same stimuli and depend upon the same signaling pathways as type I IFN. For example, type III IFN has been shown to be induced by a variety of viruses such as influenza A virus, herpes viruses, and Sendai virus as well as lipopolysaccharides or double-stranded RNA (9 -11). However, the contribution of different cell populations to the production of IFN-is not yet clear. An important difference between the type I and III IFN systems is the expression pattern of their receptors. Whereas most cell types express the type I IFN receptor complex and the IL-10R2 component of the IFN-receptor, the expression of the IFN-R1 receptor subunit is highly restricted (12, 13). The exact expression pattern of the IFN-R1 is not yet fully established, but it is clear that cells of epithelial origin express IFN-R1 (13). Because type III IFN cannot signal without both receptor subunits, the response to type III IFN is restricted as well. Recent work, using IFN-R1 knock-out mice, demonstrated that IFN-is effective against influenza virus, if the virus is administrated through the intranasal route, b...

Structure and function of interleukin-22 and other members of the interleukin-10 family

“…A similar dimeric conformation has been described for IFN-c [6,13]. Alternatively, depending on the length and flexibility of the DE loop [26] and/or the orientation promoted by additional disulfide bridges [23], all the six to seven helices can fold up as an individual monomer, as Fig. 1 Alignment of the IL-10 family member amino acid sequences.…”

“…IL-20 and IL-24 are very similar to IL-19, with 39 and 30% of amino acid identity with IL-19, respectively, thereby forming another cluster. IL-10 and IL-26 share relatively high identity (24%) and are also proposed to form a separate cluster within the IL-10 family, whereas IL-22 seems to be relatively more closely related to the IFN-ks than the other IL-10 family members [23].…”

“…The crystal structures of IL-10 [6,7], IL-19 [24], IL-22 [8,25], and, more recently, IFN-k3 [23] have been determined. Based on the information extracted from these 3D structures, as well as sequence alignments and secondary structure prediction, one can draw several conclusions about IL-10 family members' secondary, tertiary, and quaternary organization.…”

“…A four-helix bundle, generally formed by helices A, C, D, and F, comprises the protein core, which is a characteristic feature of all these helical cytokines [13,23,24,26]. Despite the partially conserved cysteine positions among the members of the IL-10 family, the organizations of the disulfide networks are quite different, as revealed by the crystal structures of IL-10, IL-19, IL-22, and IFN-k3.…”

“…From the quaternary structure point of view, IL-10 family members can be found either as monomers [8,23,24] or intimately intertwined dimers [6,13]. The preference for dimer or monomer formation is most probably a consequence of S-S interactions with the DE loop and/or the length of this loop.…”