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Molecular and Cellular Biology, September 2009, p. 4778-4787, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.01808-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Receptor Density Is Key to the Alpha2/Beta Interferon Differential Activities{triangledown}

Ignacio Moraga,1 Daniel Harari,2 Gideon Schreiber,2 Gilles Uzé,3,{dagger} and Sandra Pellegrini1,{dagger}*

Institut Pasteur, Unit of Cytokine Signaling, CNRS URA 1961, Paris, France,1 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel,2 CNRS UMR 5235, Montpellier, France3

Received 26 November 2008/ Returned for modification 6 February 2009/ Accepted 18 June 2009

Multiple type I interferons (IFN-{alpha}/β) 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}/β 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-β was more potent than IFN-{alpha}2 in antiproliferative activity, while the two subtypes were equipotent in all other readouts. Conversely, in cells with abundant receptors, IFN-{alpha}2 matched or even surpassed IFN-β 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.

* Corresponding author. Mailing address: Unit of Cytokine Signaling, Institut Pasteur, 25 rue du Docteur Roux, Paris 75724, Cedex 15, France. Phone: 33 1 4061 3305. Fax: 33 1 4061 3204. E-mail: pellegri{at}pasteur.fr

{triangledown} Published ahead of print on 29 June 2009.

{dagger} G.U. and S.P. share senior coauthorship.

Molecular and Cellular Biology, September 2009, p. 4778-4787, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.01808-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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