Inhibition by phorbol esters of antiimmunoglobulin-induced calcium signalling and B-cell activation

Abstract

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.