Activation of protein kinase A (PKA) in B lymphocytes prior to the ligation of the B cell antigen receptor (BCR) results in a profound inhibition of BCR induced proliferation. The major effect of increased PKA activity in B lymphocytes was the induction of apoptosis leading to a reduced BCR induced growth response. The growth promoting cytokine IL-4 rescued B lymphocytes from PKA mediated negative effects. IL-4 protected BCR stimulated cells from PKA mediated inhibition primarily by preventing apoptosis and growth arrest. PKA-activation caused a downregulation of anti-IgM induced expression of Bcl-x(L) protein, that was restored by IL-4. Previous studies have shown that PKA-activation blocks BCR induced phospholipase Cγ- activation and calcium mobilization. IL-4 was unable to overcome the block in anti-IgM mediated calcium mobilization due to PKA-activation. B cell apoptosis induced by PKA-activation was also seen in CD72 stimulated cells, although CD72 mediated B-lymphocyte proliferation was not affected. PKA mediated block in phospholipase γ-activation and calcium mobilization were not due to alterations in the activation of tyrosine kinases lyn, blk and syk. Moreover, BCR mediated tyrosine phosphorylation of PLC γ2 and CD19 were also unaffected by cAMP accumulation. These observations are in contrast to the ability of PKA to drastically reduce the activity of ZAP-70 and syk in T lymphocytes and neutrophils, respectively. The IL-4 mediated protection appears to be due to a change in late events in BCR signaling, which are important for Bcl-x(L) expression.
|Number of pages||18|
|State||Published - Oct 1 1998|
Bibliographical noteFunding Information:
In the present study we examined whether cAMP modulated the early signaling events through the BCR, which can account for the cAMP-induced reduction in PLC activation and calcium mobilization as seen in our earlier report ( Muthusamy et al., 1991 ). Also, we studied the mechanisms by which IL-4 signaling overrides the negative effects of cAMP accumulation in B cells. Our data show that elevation of cAMP does not alter the profile of tyrosine phosphorylated proteins normally seen after BCR ligation. This conclusion is supported by the inability of elevated cAMP levels to block BCR mediated activation of PTKs lyn, blk and syk. Thus, in B cells, these PTKs are insensitive to the inhibitory effects of PKA activation. These findings are in contrast to the effects seen in the early signaling events in T lymphocytes after anti-CD3 stimulation ( Ohtsuka et al., 1996 ), where cAMP elevation results in inhibition of ras activation and tyrosine phosphorylation of ZAP-70 and PLC γ 1 ( Ohtsuka et al., 1996 ).
- B lymphocytes
- Protein Kinase A
ASJC Scopus subject areas
- Molecular Biology