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R L Roper

Publications and source records attributed to R L Roper.

5 recordsLinked to original sources
PubMed1992

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)

Animals↗
PubMed1991

A new view of prostaglandin E regulation of the immune response.

Prostaglandins, particularly those of the E series, are widely regarded as immunosuppressive products of eukaryotic cells that can downregulate many aspects of B- and T-cell function. In this article, Richard Phipps and colleagues present a different concept of E series prostaglandins, based on recent evidence supporting a role for prostaglandins as potentiators of immunoglobulin class switching and of the synthesis of selected cytokines and cytokine receptors.

Animals↗
PubMed1990

Prostaglandin E2 promotes IL-4-induced IgE and IgG1 synthesis.

PG of the E series are generally known to suppress immune responses, however, we have found that PGE synergizes with IL-4 to induce IgE and IgG1 production in LPS-stimulated murine B lymphocytes. PGE2 and PGE1 (10(-6) to 10(-8) M) significantly increase IgE and IgG1 production (up to 26-fold) at all concentrations of IL-4 tested. In addition to its effects on IgE and IgG1, PGE also causes a significant decrease in IgM and IgG3 synthesis, suggesting that PGE may promote IL-4-induced class switching. The specificity of the E series PG effect is demonstrated by the fact that PGF2 alpha (10(-6) M) does not alter production of any of these isotypes. Because PGE can mediate its effects through cAMP in some cases, we investigated the importance of cAMP levels in regulation of isotype expression. Other agents that increase intracellular cAMP levels (cholera toxin and dibutyryl cAMP) were assessed for their ability to regulate isotype differentiation. Cholera toxin (100 pg/ml) and dibutyryl cAMP (100 microM) significantly enhanced IgE and IgG1 production and diminished IgM and IgG3 synthesis. We also show that PGE and cholera toxin elevate intracellular cAMP in B lymphocytes in a dose-dependent manner. In contrast, PGF2 alpha (10(-6) M) and the B subunit of cholera toxin (100 pg/ml) did not increase cAMP and did not regulate the isotype of Ig produced, reiterating the importance of cAMP in enhancing isotype differentiation. Although PGE is known to inhibit a number of immune responses, our data show that it is not always inhibitory. PGE may play a role in atopy in vivo where PGE-secreting cells such as macrophages, follicular dendritic cells, and fibroblasts can promote IgE synthesis. This research emphasizes the importance of PGE in regulation of the humoral immune response and adds a new stimulatory action to the repertoire of known PGE effects.

Alprostadil↗
PubMed1990

Regulation of B-cell tolerance and triggering by macrophages and lymphoid dendritic cells.

This review explores the concept that accessory cells differentially regulate immune responses such that tolerance or immunity is induced. Macrophages and lymphoid dendritic cells differentially present hapten-conjugated Ig, antigen-antibody complexes and hapten-modified self such that hapten-specific B-cell development into IgM-secreting cells is blocked or stimulated. The mechanism by which macrophages inhibit B-lymphocyte differentiation is dependent upon an antigen-specific signal and a second nonspecific signal supplied by macrophage-derived E-series PG. In contrast, non PGE-producing lymphoid dendritic cells promoted maturation to IgM PFC by acting as a powerful stimulator of T-lymphocyte IL-2 production. PGE2, but not the structurally similar compound PGF2 alpha, synergized with ligands (e.g. antigen-antibody complexes) which cross-link B-cell sIg or both sIg and Fc receptors to promote hapten-specific unresponsiveness to thymus-independent antigens. Murine B lymphomas were also tested for sensitivity to E- and F-series PG. These cells varied in sensitivity to PGE2 and PGE1 in terms of growth inhibition, suggesting heterogeneity in B-cell PG responsiveness. Interestingly, E-series PG synergized with anti-Ig reagents to kill B lymphomas representative of "immature" normal B cells. In contrast to the effects of PGE on IgM production, we discovered that E-, but not F-series, PG promoted B-cell isotype switching to IgE and IgG1 in the presence of IL-4 and the polyclonal B-cell activator LPS. Other agents which stimulate a cAMP response also promoted isotype switching. These observations indicate that PGE are not obligatory inhibitors of immune responses. Research is in progress to uncover the molecular mechanisms by which PGE are "positive" or "negative" regulators of B lymphocytes.

Animals↗