Bruton's tyrosine-kinase-deficient murine B lymphocytes fail to enter S phase when stimulated with anti-immunoglobulin plus interleukin-4.
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 (BtkM) mice. Upon stimulation with anti-IgM and IL-4, BtkM 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 G1 stage. They down-regulate the cyclin-dependent kinase ( cdk) inhibitor p27 to some extent but fail to up-regulate the G1-phase cyclins D2 and E and the retinoblastoma protein (pRb) remains hypo-phosphorylated. While approximately 25% of the wild-type cells enter S phase after 36 h stimulation, only 1% of the BtkM cells do so. The proliferative responsiveness of the BtkM 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 G1 phase due to inadequate activation of a pathway that regulates PKC activation.[1]References
- Bruton's tyrosine-kinase-deficient murine B lymphocytes fail to enter S phase when stimulated with anti-immunoglobulin plus interleukin-4. Forssell, J., Nilsson, A., Sideras, P. Scand. J. Immunol. (1999) [Pubmed]
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