Bimodal effect of phorbol ester on B cell activation. Implication for the role of protein kinase C.
The role of protein kinase C PKC in B cell activation is controversial. These studies were undertaken to determine whether protein kinase C has a stimulatory or inhibitory role in B cell activation. We found that treatment of B cells for a short period of time (30 min) with the PKC activator phorbol 12,13-dibutyrate (PDBU) primed the cells for enhanced proliferative responses to anti-immunoglobulin (anti-Ig) antibody whereas treatment for a longer period of time (3 h or more) resulted in suppression of proliferation. The enhanced proliferative response to treatment of B cells with PDBU for short periods of time was associated with inhibition of anti-Ig-stimulated increases in phosphatidyl 4,5-bisphosphate (PIP2) hydrolysis and inhibition of increases in [Ca2+]i, indicating that activation of PKC per se might be sufficient for enhancing B cell activation. The time-dependent effect of phorbol esters on the inhibition of B cell proliferation was found to be closely correlated with the kinetics of disappearance of PKC as measured by Western blot and by enzymatic activity but not with inhibition of [Ca2+]i and PIP2. These data demonstrate a bimodal time-dependent effect of PDBU on B cell activation and suggest that (a) the inhibitory effect of phorbol ester on anti-Ig-induced proliferation may be due to the disappearance of PKC rather than to the inhibition of PIP2 and Ca2+; and (b) the early activation of PKC is a stimulatory rather than an inhibitory signal in the induction of B lymphocyte proliferation by anti-Ig.
Mond
J J
JJ
Department of Medicine, Uniformed Services University of the Health Services, Bethesda, Maryland 20814.
Feuerstein
N
N
June
C H
CH
Balapure
A K
AK
Glazer
R I
RI
Witherspoon
K
K
Brunswick
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008811:Mice, Inbred DBA; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D019311:Staurosporine; D013997:Time Factors
D000470:Alkaloids; D007546:Isoquinolines; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D010879:Piperazines; D015240:Phorbol 12,13-Dibutyrate; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine; D002118:Calcium