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Bruton's Tyrosine‐Kinase‐Deficient Murine B Lymphocytes Fail to Enter S Phase when Stimulated with Anti‐Immunoglobulin Plus Interleukin‐4
Author(s) -
Forssell,
Mats Nilsson,
Sideras
Publication year - 1999
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1046/j.1365-3083.1999.00483.x
Subject(s) - bruton's tyrosine kinase , protein kinase c , biology , tyrosine kinase , microbiology and biotechnology , antibody , kinase , immunology , signal transduction , cancer research
One of the earliest recognized defects of B cells carrying the xid mutation in the gene encoding for Bruton's tyrosine kinase (Btk) was their inability to proliferate in response to anti‐immunoglobulin plus interleukin (IL)‐4 stimulation. Previous attempts to define the stage at which this proliferative block occurred using xid B cells provided dissimilar results. We decided to reinvestigate this question using B cells from C57BL/6‐Btk‐protein‐deficient (Btk M ) mice. Upon stimulation with anti‐IgM and IL‐4, Btk M cells increase in size and up‐regulate early activation markers such as CD69 and B7‐2, however, they do not progress into the cell cycle further than a very early G 1 stage. They down‐regulate the cyclin‐dependent kinase (cdk) inhibitor p27 to some extent but fail to up‐regulate the G 1 ‐phase cyclins D2 and E and the retinoblastoma protein (pRb) remains hypo‐phosphorylated. While ≈ 25% of the wild‐type cells enter S phase after 36 h stimulation, only ≈ 1% of the Btk M cells do so. The proliferative responsiveness of the Btk M cells is restored when the phorbol ester phorbol 12,13‐di‐butyrate (PDBu) is added to the anti‐IgM plus IL‐4 cultures. Collectively, our data demonstrate that a dramatically reduced frequency of responsive cells underlies the low proliferation of anti‐IgM plus IL‐4‐stimulated Btk‐deficient B cells and point towards an early block in the G 1 phase due to inadequate activation of a pathway that regulates PKC activation.