title: Receptor density is key to the alpha2/beta interferon differential activities.
abstract: Multiple type I interferons (IFN-alpha/beta) elicit Jak/Stat activation, rapid gene induction, and pleiotropic effects, such as differentiation, antiviral protection, and blocks in proliferation, which are dependent on the IFN subtype and the cellular context. To date, ligand- and receptor-specific molecular determinants underlying IFN-alpha/beta differential activities or potencies have been well characterized. To analyze cellular determinants that impact subtype-specific potency, human fibrosarcoma U5A-derived clones, exhibiting a gradient of IFN sensitivity by virtue of increasing receptor levels, were monitored for Jak/Stat signaling, gene induction, cell cycle lengthening, and apoptosis. In cells with scarce receptors, IFN-beta was more potent than IFN-alpha2 in antiproliferative activity, while the two subtypes were equipotent in all other readouts. Conversely, in cells with abundant receptors, IFN-alpha2 matched or even surpassed IFN-beta in all readouts tested. Our results suggest that the differential activities of the IFN subtypes are dictated not only by the intrinsic ligand/receptor binding kinetics but also by the density of cell surface receptor components.
authors: Institut Pasteur, Unit of Cytokine Signaling, CNRS URA 1961, Paris, France.
authors: Ignacio
authors: I
authors: Moraga
authors: Daniel
authors: D
authors: Harari
authors: Gideon
authors: G
authors: Schreiber
authors: Gilles
authors: G
authors: Uzé
authors: Sandra
authors: S
authors: Pellegrini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D050791:STAT Transcription Factors; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D053612:Janus Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human