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J. Biol. Chem., Vol. 279, Issue 31, 32269-32274, July 30, 2004

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Role of the Interleukin (IL)-28 Receptor Tyrosine Residues for Antiviral and Antiproliferative Activity of IL-29/Interferon-1

SIMILARITIES WITH TYPE I INTERFERON SIGNALING^*

Laure Dumoutier, Amel Tounsi, Thomas Michiels¶, Caroline Sommereyns¶||, Sergei V. Kotenko**, and Jean-Christophe Renauld

From the Ludwig Institute for Cancer Research, Brussels Branch and the Experimental Medicine Unit, Université de Louvain, B-1200 Brussels, Belgium, the ^¶MIPA-VIRO Unit, Christian de Duve Institute of Cellular Pathology, Université de Louvain, B-1200 Brussels, Belgium, and the ^**Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

Interferon (IFN)-1, -2, and -3 are the latest members of the class II cytokine family and were shown to have antiviral activity. Their receptor is composed of two chains, interleukin-28R/likely interleukin or cytokine or receptor 2 (IL-28R/LICR2) and IL-10R, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs. We used IL-28R/LICR2-mutated receptors to identify the tyrosines required for STAT activation, as well as antiproliferative and antiviral activities. We found that IFN-1-induced STAT2 tyrosine phosphorylation is mediated through tyrosines 343 and 517 of the receptor, which showed some similarities with tyrosines from type I IFN receptors involved in STAT2 activation. These two tyrosines were also responsible for antiviral and antiproliferative activities of IFN-1. By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues. Taken together, these observations extend the functional similarities between IFN-s and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.

Received for publication, April 29, 2004 , and in revised form, May 26, 2004.

^* This work was supported in part by the Belgian Federal Service for Scientific, Technical and Cultural Affairs, and the Actions de Recherche Concertées, Communauté Française de Belgique, as well as by United States Public Health Services Grant RO1 AI51139 from the NIAID, National Institutes of Health, and by American Heart Association Grant AHA 0245131N (to S. V. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Research fellow with the Fonds National de la Recherche Scientifique, Belgium.

^|| Received a Ph.D fellowship from the Fonds pour la Formation a la Recherche Fondamentale dans l'Industrie et l'Agriculture, Belgium.

To whom correspondence should be addressed: Ludwig Inst. for Cancer Research, Avenue Hippocrate, 74, B-1200 Brussels, Belgium. Tel.: 32-2-764-74-64; Fax: 32-2-762-94-05; E-mail: renauld{at}licr.ucl.ac.be.

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