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

• Published in: The Journal of biological chemistry Vol. 281; no. 24; pp. 16238 - 16244
• Main Authors: Gamero, Ana M., Potla, Ramesh, Wegrzyn, Joanna, Szelag, Magdelena, Edling, Andrea E., Shimoda, Kazuya, Link, Daniel C., Dulak, Jozef, Baker, Darren P., Tanabe, Yoshinari, Grayson, Jason M., Larner, Andrew C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.06.2006
• Subjects: Animals; Annexin A5 - metabolism; Apoptosis; B-Lymphocytes - metabolism; Cytoplasm - metabolism; Immunoblotting; Interferon-beta - metabolism; Interleukin-7 - metabolism; Lymphocytic choriomeningitis virus; Mice; Mice, Transgenic; Phosphorylation; Protein-Tyrosine Kinases - chemistry; STAT3 Transcription Factor - metabolism; TYK2 Kinase; Tyrosine - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M509516200

The growth-inhibitory effects of type 1 interferons (IFNs) (IFNα/β) 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 IFNβ, but not IFNα, induces programmed cell death (PCD). IFNβ-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, IFNβ-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 IFNα/β (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 IFNα/β-mediated PCD. In contrast to IFNβ-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 IFNβ. Furthermore, expression of a constitutively active form of Stat3 in Tyk2–/– B cells partially restores IFNβ-stimulated PCD. These results demonstrate an important role of Tyk2-mediated tyrosine phosphorylation of Stat3 in the ability of IFNβ to stimulate apoptosis of primary pro-B cells.