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J. Biol. Chem., Vol. 281, Issue 24, 16238-16244, June 16, 2006

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Activation of Tyk2 and Stat3 Is Required for the Apoptotic Actions of Interferon- in Primary Pro-B Cells^*

Ana M. Gamero, Ramesh Potla^¶, Joanna Wegrzyn^||, Magdelena Szelag^||, Andrea E. Edling, Kazuya Shimoda^**, Daniel C. Link, Jozef Dulak^||, Darren P. Baker, Yoshinari Tanabe^¶¶, Jason M. Grayson^||||, and Andrew C. Larner¹

From the Laboratory of Experimental Immunology, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, the Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, ^**Medicine and Biosystemic Science, Kyushu University, 812-8582 Fukuoka, Japan, the Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, the ^||Department of Medical Biotechnology, Jagiellonian University, 30-387 Krakow, Poland, the ^¶Department of Biology, Cleveland State University, Cleveland, Ohio 44195, Biogen Idec Inc., Cambridge, Massachusetts 02142, the ^||||Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, and the ^¶¶Department of Medicine, Niigata University School of Medicine, Niigata, 951-8510 Japan

The growth-inhibitory effects of type 1 interferons (IFNs) (IFN/) are complex, and the role of apoptosis in their antigrowth effects is variable and not well understood. We have examined primary murine interleukin-7-dependent bone marrow-derived pro-B cells, where IFN, but not IFN, induces programmed cell death (PCD). IFN-stimulated apoptosis is the same in pro-B cells derived from wild type and Stat1^–/– mice. However, in pro-B cells from Tyk2^–/– mice, where there is normal activation of Stat1 and Stat2, IFN-stimulated PCD is not observed. Loss of B cells in lymphocytic choriomeningitis virus-infected mice has been shown to be mediated through the expression of IFN/ (1). In wild type mice infected with lymphocytic choriomeningitis virus, there is a greater loss of B cells in the bone marrow and spleen than in Tyk2^–/– mice infected with the virus, suggesting that the expression of this kinase plays an in vivo role in IFN/-mediated PCD. In contrast to IFN-stimulated tyrosine phosphorylation of Stat1 and Stat2, Stat3 tyrosine phosphorylation is defective in Tyk2^–/– pro-B cells, suggesting that this Stat family member is required for apoptosis. In support of this hypothesis, inhibition of Stat3 activation in wild type B cells reverses the apoptotic effects of IFN. Furthermore, expression of a constitutively active form of Stat3 in Tyk2^–/– B cells partially restores IFN-stimulated PCD. These results demonstrate an important role of Tyk2-mediated tyrosine phosphorylation of Stat3 in the ability of IFN to stimulate apoptosis of primary pro-B cells.

Received for publication, August 29, 2005 , and in revised form, April 4, 2006.

^* 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.

¹ To whom correspondence should be addressed: Dept. of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-9045; Fax: 216-444-8372; E-mail: larnera{at}ccf.org.

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