Glucocorticoids suppress calcium mobilization and phospholipid hydrolysis in anti-Ig antibody-stimulated B cells.
Glucocorticoids have been shown to play a major role in influencing the activation of B lymphocytes. In view of our recent observation that dexamethasone exerts a marked suppressive effect on an early event in B cell activation that is stimulated by anti-Ig antibody, we investigated its activity on other stimuli that induce intracellular events similar to those produced by anti-Ig antibody. Because the intracellular events that occur after B cell stimulation with phorbol myristate acetate and the calcium ionophore A23187 appear to mimic those that occur after B cell stimulation with anti-Ig antibody, we studied whether the cellular responses elicited by these activation stimuli are affected in a similar fashion by dexamethasone. Whereas anti-Ig antibody-stimulated entry of G0 B cells to the G1 and S phase of the cell cycle was markedly suppressed by dexamethasone, phorbol myristate acetate/A23187 stimulation of these events was resistant to dexamethasone. Our finding that anti-Ig-induced cross-linking of B cell surface Ig, as measured by surface Ig capping, was not inhibited by dexamethasone suggested that corticosteroids inhibit anti-Ig-induced B cell proliferation at a step distal to membrane Ig cross-linking and proximal to phosphatidylinositol bisphosphate hydrolysis. This hypothesis is supported by experiments presented in this manuscript which demonstrate that dexamethasone inhibits anti-Ig-stimulated phosphatidylinositol bisphosphate hydrolysis. We also found that dexamethasone markedly inhibited anti-Ig antibody-stimulated increases in intracellular ionized calcium concentrations. This dexamethasone-mediated suppression is time-dependent as it is not seen when B cells are cultured with dexamethasone for less than 6 hr. Our data suggest that the immunomodulatory activity of glucocorticoids is exerted by binding to its nuclear receptor, thereby preventing the generation of second messengers required for cell activation after agonist-receptor interaction.
Dennis
G
G
Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20014.
June
C H
CH
Mizuguchi
J
J
Ohara
J
J
Witherspoon
K
K
Finkelman
F D
FD
McMillan
V
V
Mond
J J
JJ
D000818:Animals; D000888:Antibodies, Anti-Idiotypic; D000937:Antigen-Antibody Reactions; D001402:B-Lymphocytes / Q000502:physiology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D005938:Glucocorticoids; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011947:Receptors, Antigen, B-Cell; D011965:Receptors, Glucocorticoid; D000001:Calcimycin; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium