title: Multifaceted activities of type I interferon are revealed by a receptor antagonist.
abstract: Type I interferons (IFNs), including various IFN-α isoforms and IFN-β, are a family of homologous, multifunctional cytokines. IFNs activate different cellular responses by binding to a common receptor that consists of two subunits, IFNAR1 and IFNAR2. In addition to stimulating antiviral responses, they also inhibit cell proliferation and modulate other immune responses. We characterized various IFNs, including a mutant IFN-α2 (IFN-1ant) that bound tightly to IFNAR2 but had markedly reduced binding to IFNAR1. Whereas IFN-1ant stimulated antiviral activity in a range of cell lines, it failed to elicit immunomodulatory and antiproliferative activities. The antiviral activities of the various IFNs tested depended on a set of IFN-sensitive genes (the "robust" genes) that were controlled by canonical IFN response elements and responded at low concentrations of IFNs. Conversely, these elements were not found in the promoters of genes required for the antiproliferative responses of IFNs (the "tunable" genes). The extent of expression of tunable genes was cell type-specific and correlated with the magnitude of the antiproliferative effects of the various IFNs. Although IFN-1ant induced the expression of robust genes similarly in five different cell lines, its antiviral activity was virus- and cell type-specific. Our findings suggest that IFN-1ant may be a therapeutic candidate for the treatment of specific viral infections without inducing the immunomodulatory and antiproliferative functions of wild-type IFN.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Levin
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Schneider
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Hoffmann
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ganit
authors.initials: G
authors.lastname: Yarden
authors.affiliation: Automatic Control Laboratory, ETH Zurich, 8092 Zurich, Switzerland.
authors.forename: Alberto Giovanni
authors.initials: AG
authors.lastname: Busetto
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ohad
authors.initials: O
authors.lastname: Manor
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nanaocha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. gideon.schreiber@weizmann.ac.il.
authors.forename: Gideon
authors.initials: G
authors.lastname: Schreiber
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D016000:Cluster Analysis; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D025341:Principal Component Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D014777:Virus Diseases / Q000276:immunology*
chemical_list: C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D007370:Interferon Type I; D034741:RNA, Small Interfering; D053633:Receptor, Interferon alpha-beta