Interleukin-4 overcomes the negative influence of cyclic AMP accumulation on antigen receptor stimulated B lymphocytes

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 B CR induced proliferation. The major effect of increased PKA activity in B l ymphocytes was the induction of apoptosis leading to a reduced BCR induced growth response. The growth promoting cytokine IL-4 rescued B lymphocytes f rom PKA mediated negative effects. IL-4 protected BCR stimulated cells from PKA mediated inhibition primarily by preventing apoptosis and growth arres t. 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 t hat PKA-activation blocks BCR induced phospholipase C gamma-activation and calcium mobilization. IL-4 was unable to overcome the block in anti-IgM med iated calcium mobilization due to PKA-activation. B cell apoptosis induced by PKA-activation was also seen in CD72 stimulated cells, although CD72 med iated B-lymphocyte proliferation was not affected. PKA mediated block in ph ospholipase gamma-activation and calcium mobilization were not due to alter ations in the activation of tyrosine kinases lyn, blk and syk. Moreover, BC R mediated tyrosine phosphorylation of PLC gamma 2 and CD19 were also unaff ected by cAMP accumulation. These observations are in contrast to the abili ty of PKA to drastically reduce the activity of ZAP-70 and syk in T lymphoc ytes and neutrophils, respectively. The IL-4 mediated protection appears to be due to a change in late events in BCR signaling, which are important fo r Bcl-x(L) expression. (C) 1998 Elsevier Science Ltd. All rights reserved.