IL-28B (also named interferon-lambda 3, IFN-lambda 3), IL-28A (IFN-lambda 2) and IL-29 (IFN-lambda 1) are type III interferons that are class II cytokine receptor ligands. They are distantly related to members of the IL-10 family and type I IFN family. Human IL-28B cDNA encodes a 200 amino acid (aa) protein with a 25 aa signal peptide and a 175 aa mature protein that lacks N-glycosylation sites. Mature human IL-28B shares 64% and 75% aa sequence identity with mouse and canine IL-28B, respectively, and is active across species. Human IL-28B shares 94% and 69% aa identity with human IL-28A and IL29, respectively. Type III interferons are widely expressed, but are mainly produced by antigen presenting cells in response to viruses and double-stranded RNA that interact with Toll-like receptors or RIG-1 family helicases. They signal through a widely expressed receptor that is a heterodimer of the IL-10 receptor beta (IL-10 R beta ) and IL-28 receptor alpha (IL-28 R alpha ; also called IFN-lambda R1). Interaction of either type I or type III IFNs with their receptors activates similar pathways, including JAK tyrosine kinase activation, STAT phosphorylation and formation of the IFN-stimulated regulatory factor 3 (ISGF-3) transcription factor complex. Both type I and III IFNs induce antiviral activity and upregulate MHC class I antigen expression. Cell lines responsive to type III IFNs are also responsive to type I IFNs, but in general, higher concentrations of type III IFNs are needed for similar in vitro responses. In vivo, however, type III IFNs enhance levels of IFN-gamma in serum, suggesting that the robust anti-viral activity of type III IFNs may stem in part from activation of the immune system. Anti-proliferative and antitumor activity in vivo has also been shown for type III IFNs.