Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-β 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, Andrew C. Larner

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)16238-16244
Number of pages7
JournalJournal of Biological Chemistry
Volume281
Issue number24
DOIs
StatePublished - Jun 16 2006

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