Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells.
The growth-inhibitory effects of type 1 interferons (IFNs) (IFNalpha/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 IFNbeta, but not IFNalpha, induces programmed cell death (PCD). IFNbeta-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, IFNbeta-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 IFNalpha/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 IFNalpha/beta-mediated PCD. In contrast to IFNbeta-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 IFNbeta. Furthermore, expression of a constitutively active form of Stat3 in Tyk2(-/-) B cells partially restores IFNbeta-stimulated PCD. These results demonstrate an important role of Tyk2-mediated tyrosine phosphorylation of Stat3 in the ability of IFNbeta to stimulate apoptosis of primary pro-B cells.
Gamero
Ana M
AM
Laboratory of Experimental Immunology, NCI-Frederick, National Institutes of Health, Frederick, MD 21702, USA.
Potla
Ramesh
R
Wegrzyn
Joanna
J
Szelag
Magdelena
M
Edling
Andrea E
AE
Shimoda
Kazuya
K
Link
Daniel C
DC
Dulak
Jozef
J
Baker
Darren P
DP
Tanabe
Yoshinari
Y
Grayson
Jason M
JM
Larner
Andrew C
AC
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D015151:Immunoblotting; D016899:Interferon-beta / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D053634:TYK2 Kinase; D014443:Tyrosine / Q000737:chemistry
D017304:Annexin A5; D015851:Interleukin-7; D050796:STAT3 Transcription Factor; D014443:Tyrosine; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse