Fine Tuning of a Type 1 Interferon Antagonist

• Published in: PloS one Vol. 10; no. 7; p. e0130797
• Main Authors: Urin, Victoria, Levin, Doron, Sharma, Nanaocha, Harari, Daniel, Schreiber, Gideon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.07.2015; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Animals; Autoimmune diseases; Binding; Biological response modifiers; Blotting, Western; Cancer; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cognitive ability; Cytokines; Encephalomyocarditis virus - drug effects; Gene expression; Gene Expression - drug effects; Genomics; Humans; Interferon; Interferon Type I - antagonists & inhibitors; Interferon Type I - genetics; Interferon Type I - metabolism; Kinases; Ligands; Mice, Inbred C57BL; Multiple sclerosis; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutant Proteins - pharmacology; Mutation; Phosphorylation; Phosphorylation - drug effects; Protein Binding - drug effects; Proteins; Receptor, Interferon alpha-beta - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Science; STAT1 Transcription Factor - metabolism; STAT2 Transcription Factor - metabolism; Transcription; Tuberculosis; Vesicular stomatitis Indiana virus - drug effects; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0130797

Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.