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J. Biol. Chem., Vol. 279, Issue 5, 3245-3253, January 30, 2004

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Cells Previously Desensitized to Type 1 Interferons Display Different Mechanisms of Activation of Stat-dependent Gene Expression from Naïve Cells^*

Shuji Sakamoto, Jinzhong Qin, Angels Navarro, Ana Gamero, Ramesh Potla, Taolin Yi, Wei Zhu, Darren P. Baker¶, Gerald Feldman||, and Andrew C. Larner**

From the Department of Immunology, Lerner Research Institute and the Department of Cancer Biology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, ^¶Biogen Inc., Cambridge, Massachusetts 02142, and the ^||Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Over the past decade, a wealth of knowledge has been obtained concerning the mechanisms by which interferons (IFNs) and other cytokines activate or down-regulate immediate early genes via the Jak/Stat pathway. In contrast, little information is available on interferon-activated gene expression in naïve cells compared with cells that have been desensitized and subsequently resensitized to the actions of these cytokines. In naïve cells, the ISG54 gene is activated via IFN-stimulated formation of ISGF3, a heterotrimeric DNA binding complex consisting of p48 (IRF9) and tyrosine-phosphorylated Stat1 and Stat2. In contrast, in previously desensitized cells IFN weakly stimulates the assembly of an ISGF3-like complex that lacks Stat1, even though ISG54 mRNA induction is the same as in naïve cells. The lack of Stat1 tyrosine phosphorylation and DNA binding is due to increased activity of a protein-tyrosine phosphatase. In cells that do not express the tyrosine phosphatase Tc-PTP, the rate of Stat1 dephosphorylation is the same in naïve and previously desensitized cells. These results implicate Tc-PTP in a novel role in the regulation of type 1 interferon-stimulated gene expression.

Received for publication, August 29, 2003 , and in revised form, October 22, 2003.

^* This work was supported by National Institutes of Health Grant CA77366 and a fellowship (to S. S.) from the Vehara Memorial Foundation. 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.

^** To whom correspondence should be addressed: Dept. of Immunology, Lerner Research Institute, 9500 Euclid Ave., Cleveland, OH 44195. E-mail: larnera{at}ccf.iorg.

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