Prostaglandin E2 and cAMP inhibit B lymphocyte activation and simultaneously promote IgE and IgG1 synthesis.
Macrophage-secreted prostaglandins of the E series inhibit numerous immunologic events, including IgM secretion by B lymphocytes. In this study, we investigated whether PGE also regulates the activation of normal quiescent murine B cells and subsequent isotype differentiation to IgE and IgG1 production. PGE2 and PGE1 were found to inhibit cellular enlargement induced by IL-4 or bacterial LPS, IL-4 and LPS, or anti-mu and IL-4 by approximately 75%, and completely inhibit enlargement in response to anti-mu antibody. PGE2 also suppresses activation-induced class II MHC up-regulation by 35% and expression of the low affinity IgE receptor, Fc epsilon RII/CD23, by 30%. Interestingly, PGE completely inhibits a fraction of cells from these activation events, while other cells fully respond to activation stimuli, even in the presence of high PGE2 concentrations. Therefore, a PGE-resistant subset of B lymphocytes may exist. A closely related PG, PGF2 alpha, had no immunoregulatory effect in these systems. Because PGE induces production of cAMP in B cells, we determined whether other agents that increase cAMP could inhibit B cell activation. Cholera toxin and dibutyryl cAMP mimicked the ability of PGE2 to inhibit B cell enlargement, and class II MHC and Fc epsilon RII induction, suggesting that PGE2 signaling occurs via cAMP. In addition, cholera toxin and dibutyryl cAMP inhibited B cell activation much more potently (90-100% inhibition) than PGE, indicating that whereas all B cells are cAMP-sensitive only some are PGE-sensitive. Although PGE inhibits activation-associated events, we previously reported that PGE enhances IL-4 and LPS-induced differentiation to IgE and IgG1 synthesis. To investigate the relationship between the cells that are activation-inhibited and those that are differentiation-enhanced by PGE, we sorted B cell subsets by FACS and determined their relative abilities to produce IgM, IgG1, and IgE in response to IL-4 and LPS in the presence of PGE. The population of lymphocytes that was unaffected by PGE in terms of class II hyperexpression was also unaffected by PGE for Ig synthesis, again indicating a PGE-resistant subpopulation of B cells. Furthermore, the PGE activation-inhibited subset of B cells was responsive to PGE enhancement of IL-4-induced class switching, reducing IgM synthesis and inducing a sevenfold increase in IgE and IgG1 synthesis compared with other sort groups. These results are consistent with the hypothesis that the B lymphocytes that are PGE activation-inhibited are the same cells that are PGE differentiation-enhanced.(ABSTRACT TRUNCATED AT 400 WORDS)
Roper
R L
RL
Immunology and Immunotherapy Division, Cancer Center, University of Rochester, School of Medicine and Dentistry, NY 14642.
Phipps
R P
RP
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D005434:Flow Cytometry; D006681:HLA-D Antigens / Q000096:biosynthesis; D007111:Immunity, Cellular / Q000187:drug effects; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D017455:Receptors, IgE / Q000096:biosynthesis
D006681:HLA-D Antigens; D007074:Immunoglobulin G; D017455:Receptors, IgE; D007073:Immunoglobulin E; D003994:Bucladesine; D002772:Cholera Toxin; D015237:Dinoprost; D000242:Cyclic AMP; D015232:Dinoprostone