Background: Single nucleotide polymorphisms of the interleukin 28B (IL28B; interferon [IFN] λ3) gene are strongly associated with sustained virological response rates when treating patients with chronic hepatitis C (CHC) with PEGylated IFN and ribavirin combination therapy. However, its functional relevance in the innate immune response has not been clarified.
Methods: IFN-λ3 knockout (KO) mice were generated, and wild-type (WT) and IFN-λ3 KO mice were injected with polyinosinic-polycytidylic acid (poly[I:C]) via the tail vein. At 48 h after injection, immune cells, such as DCs, natural killer (NK) cells, and T cells, in the liver were evaluated by fluorescence-activated cell sorting analysis.
Results: To determine whether IFN-λ3 is associated with immune cell activation in vivo, WT and IFN-λ3 KO mice were stimulated with poly(I:C) and then the number of immune cells in the liver was analyzed. In IFN-λ3 KO mice, after stimulation with poly(I:C), the increase in the number of DCs, NK, and T cells in the liver was significantly lower than in WT mice. Bone marrow-derived dendritic cell (BMDCs) derived from WT or IFN-λ3 KO mice were stimulated with several type I IFN inducers. The induction of type-I IFN and cytokines (Cxcl10, Il6) was not different between WT and IFN-λ3 KO mice. However, upon stimulation with these type I IFN inducers, BMDCs derived from IFN-λ3 KO mice exhibited lower expression levels of activation markers of DCs, such as CD86 and MHC class II, than BMDCs from WT mice. These results suggested that IFN-λ3 induced DC maturation independently of type I IFN activation.
Conclusions: These results suggest that IFN-λ3 plays an important role in the DC-mediated immune response by a unique mechanism. We expect that IFN-λ3 has therapeutic potential for not just hepatitis B or C virus infections, but cancer immunotherapy in hepatocellular carcinoma as well.