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

  1. Author:
    Gamero, A. M.
    Potla, R.
    Wegrzyn, J.
    Szelag, M.
    Edling, A. E.
    Shimoda, K.
    Link, D. C.
    Dulak, J.
    Baker, D. P.
    Tanabe, Y.
    Grayson, J. M.
    Larner, A. C.

  2. Author Address

    Cleveland Clin Fdn, Dept Immunol, Lerner Res Inst, Cleveland, OH 44195 USA. NCI, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. Kyushu Univ, Fukuoka 8128582, Japan. Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. Jagiellonian Univ, Dept Med Biotechnol, PL-30387 Krakow, Poland. Cleveland State Univ, Dept Biol, Cleveland, OH 44195 USA. Biogen Idec Inc, Cambridge, MA 02142 USA. Wake Forest Univ, Sch Med, Dept Microbiol & Immunol, Winston Salem, NC 27157 USA. Niigata Univ, Sch Med, Dept Med, Niigata 9518510, Japan.;Larner, AC, Cleveland Clin Fdn, Dept Immunol, Lerner Res Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA.;larnera@ccf.org
    1. Year: 2006
    2. Date: Jun
  2. Journal: Journal of Biological Chemistry
    1. 281
    2. 24
    3. Pages: 16238-16244
  4. Type of Article: Article
  5. ISSN: 0021-9258
  1. Abstract:

    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.

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  2. DOI: 10.1074/jbc.M509516200
  3. View record in Web of Science®
  4. WOS: 000238165700009

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