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 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-xL protein, that was restored by IL-4. Previous studies have shown that PKA-activation blocks BCR induced phospholipase Cgamma-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 gamma-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 gamma2 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-xL expression.
Venkataraman
C
C
Department of Microbiology and Immunology and Sanders-Brown Center on Aging, University of Kentucky, Lexington 40536, USA.
Chelvarajan
R L
RL
Cambier
J C
JC
Bondada
S
S
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D018941:Antigens, CD19 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D006128:Growth / Q000187:drug effects; D015847:Interleukin-4 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000187:drug effects; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D051020:bcl-X Protein
D000888:Antibodies, Anti-Idiotypic; D018941:Antigens, CD19; C494812:Bcl2l1 protein, mouse; D007527:Isoenzymes; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D051020:bcl-X Protein; D015847:Interleukin-4; D014443:Tyrosine; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium