Activation of Tyk2 and Stat3 is required for the apoptotic actions of IFNbeta  in primary Pro-B cells

doi:10.1074/jbc.M509516200

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Papers In Press, published online ahead of print April 6, 2006
J. Biol. Chem, 10.1074/jbc.M509516200
Submitted on August 29, 2005
Revised on April 4, 2006
Accepted on April 6, 2006

Activation of Tyk2 and Stat3 is required for the apoptotic actions of IFN $beta$ in primary Pro-B cells

Ana M. Gamero, Ramesh Potla, Joanna Wegrzyn, Magdelana Szelag, Andrea E. Edling, Kazuya Shimoda, Daniel C. Link, Jozef Dulak, Darren P. Baker, Yoshinari Tanabe, Jason M. Grayson, and Andrew C. Larner

Immunology Dept., Cleveland Clinic Foundation, Cleveland, OH 44195

Corresponding Author: larnera{at}ccf.org

The growth inhibitory effects of type 1 IFNs (IFN?/?_) are complex, and the role of apoptosis in their antigrowth effects is variable and not well understood. We have examined primary murine IL-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 (LCMV) infected mice has been shown to be mediated through the expression of IFN?/? (1). In wild type mice infected with LCMV, 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.

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Activation of Tyk2 and Stat3 is required for the apoptotic actions of IFN in primary Pro-B cells

Activation of Tyk2 and Stat3 is required for the apoptotic actions of IFN $beta$ in primary Pro-B cells