Inhibition by phorbol esters of antiimmunoglobulin-induced calcium signalling and B-cell activation.
The inhibitory effect of phorbol dibutyrate (PDB) on B-cell stimulation was evaluated using a model in which activation is induced by modest doses of antiimmunoglobulin antibody (anti-Ig) and progression to DNA synthesis is induced by cytochalasin. PDB preferentially inhibited anti-Ig-induced activation and did so during brief (2 hr) preincubation with anti-Ig. Activation was inhibited whether PDB was added before or shortly after anti-Ig. Since activation for cytochalasin responsiveness appears to be mediated by Ca2+, the effect of PDB on the anti-Ig-induced rise in intracellular Ca2+ was evaluated. PDB (and other phorbol esters that activate protein kinase C) inhibited the rise in Ca2+ normally associated with anti-Ig treatment; moreover, PDB reversed an established anti-Ig-induced Ca2+ response. These data suggest that phorbol esters inhibit B-cell activation by interfering with the elevated levels of intracellular Ca2+ produced by cross-linking of surface immunoglobulin by anti-Ig. This could represent a "feedback inhibition" type of response, but it remains to be seen if this occurs under physiological conditions of protein kinase C activation.
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D015638:Cytochalasin D; D003572:Cytochalasins / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008805:Mice, Inbred A; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D003572:Cytochalasins; D010703:Phorbol Esters; D015638:Cytochalasin D; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D002118:Calcium