title: Comparable potency of IFNalpha2 and IFNbeta on immediate JAK/STAT activation but differential down-regulation of IFNAR2.
abstract: Type I IFNs (interferons) (IFNalpha/beta) form a family of related cytokines that control a variety of cellular functions through binding to a receptor composed of IFNAR (IFNalpha receptor subunit) 1 and 2. Among type I IFNs, the alpha2 and beta subtypes exhibit a large difference in their binding affinities to IFNAR1, and it was suggested that high concentrations of IFNAR1 may compensate for its low intrinsic binding affinity for IFNalpha2. We tested whether receptor-proximal signalling events are sensitive to IFNAR1 surface concentration by investigating the relationship between relative IFNAR1/IFNAR2 surface levels and IFNalpha2 and IFNbeta signalling potencies in several cell lines. For this, we monitored the activation profile of JAK (Janus kinase)/STAT (signal transducer and activator of transcription) proteins, measured basal and ligand-induced surface decay of each receptor subunit and tested the effect of variable IFNAR1 levels on IFNalpha2 signalling potency. Our data show that the cell-surface IFNAR1 level is indeed a limiting factor for assembly of the functional complex, but an increased concentration of it does not translate into an IFNalpha/beta differential JAK/STAT signalling nor does it change the dynamics of the engaged receptor. Importantly, however, our data highlight a differential effect upon routing of IFNAR2. Following binding of IFNalpha2, IFNAR2 is internalized, but, instead of being routed towards degradation as it is when complexed to IFNbeta, it recycles back to the cell surface. These observations suggest strongly that the stability and the intracellular lifetime of the ternary complex account for the differential control of IFNAR2. Moreover, the present study opens up the attractive possibility that endosomal-initiated signalling may contribute to IFNalpha/beta differential bioactivities.
authors.affiliation: Unité de Signalisation des Cytokines, CNRS URA 1961, Institut Pasteur, 25 rue du Docteur Roux, Paris 75724.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Marijanovic
authors.forename: Josiane
authors.initials: J
authors.lastname: Ragimbeau
authors.forename: José
authors.initials: J
authors.lastname: van der Heyden
authors.forename: Gilles
authors.initials: G
authors.lastname: Uzé
authors.forename: Sandra
authors.initials: S
authors.lastname: Pellegrini
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism*; D019169:Jurkat Cells; D008024:Ligands; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D016898:Interferon-alpha; D008024:Ligands; D050791:STAT Transcription Factors; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D053612:Janus Kinases