Type III Interferon Signaling Pathways

The type III interferon family consists of four proteins, IL-29/IFN-lambda 1, IL-28A/IFN-lambda 2, IL-28B/IFN-lambda 3, and IFN-lambda 4, which are distantly related to members of the IL-10 and type I IFN cytokine families. IL-29/IFN-lambda 1 is found only in humans and is 81% homologous to IL-28A/IFN-lambda 2 and IL-28B/IFN-lambda 3, which share 96% amino acid identity. IFN-lambda 4 was originally thought to be a pseudogene but it’s since been found that a dinucleotide frameshift variant can generate a functional IFN-lambda 4 protein. All type III IFNs bind to a receptor complex formed by the IL-28 R alpha/IFN-lambda R1 ligand-binding subunit and the IL-10 R beta accessory chain. Like type I IFNs, type III IFNs activate Jak1 and Tyk2, leading to the phosphorylation and activation of STAT1 and STAT2. Phosphorylated STAT1 and STAT2 associate with IRF9 to form the ISGF3 complex, which subsequently translocates to the nucleus and regulates the expression of ISGs. In addition, IFN-lambda proteins can also induce Jak2 phosphorylation and activate other STAT family proteins, as well as MAPK signaling pathways. Type III IFNs have similar anti-viral, anti-proliferative, apoptotic, and immunomodulatory effects as the type I IFNs and typically induce a subset of the target genes that are induced by the type I IFN-alpha and IFN-beta proteins. As IL-28 R alpha/IFN-lambda R1 is primarily expressed on epithelial cells, it has been proposed that the type III IFNs may have specifically evolved to provide anti-viral protection at epithelial surfaces.

To learn more, please visit our Interferons Research Area page