Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-β in primary pro-B cells

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