Comparative Functional Analysis of 12 Mammalian IFN-lambda 4 Orthologs

IFN-4 is a novel type-III interferon with strong clinical significance in humans. Only a subset of individualsup to 10% of Asians, 50% of Europeans, and 90% of Africanscarry the G allele of a genetic variant rs368234815-TT/G and are genetically able to produce IFN-4 protein. Carriers of the G allele have impaired ability to clear infection with hepatitis C virus (HCV). IFN-4 is also predicted to exist and be functionally important in several nonhuman mammals. In this study, we present the first comparative analysis of 12 mammalian IFN-4 orthologs in a human hepatic cell line, HepG2, which supports signaling of the human IFN-4. We show that despite differences in protein sequences, functional properties of the recombinant human and nonhuman IFN-4 proteins are comparablethey are all expressed as predominantly cytoplasmic proteins that are biologically active for induction of interferon signaling. We show that several IFN-4 orthologs can be detected by Western blotting, flow cytometry, and confocal imaging using a monoclonal antibody developed for the human IFN-4. Studies of IFN-4 in animals should help improve our understanding of the biology of this novel clinically important interferon in normal and disease conditions.