The Level of IgE Produced by a B Cell Is Regulated by Norepinephrine in a p38 MAPK- and CD23-Dependent Manner

Abstract

Although the causes of asthma vary, the severity of the disease correlates with the level of IgE produced. In this study we show that mice produced less IgE when they were depleted of the neurotransmitter norepinephrine (NE) before the administration of Ag. The suppression was prevented when a β2-adrenergic receptor (β2AR)-selective agonist was administered, suggesting that NE stimulated the β2AR to regulate the level of an IgE response in vivo. Although the cell targeted by NE to produce this effect in vivo is unknown, we show in vitro that the level of IgE increased on a per cell basis without an effect on class switch recombination when NE stimulated the β2AR on a B cell directly. The β2AR-induced increase in IgE depended on p38 MAPK but not protein kinase A activation, was due to an increased rate of mature IgE mRNA transcription, and was lost when β2AR-deficient B cells were used. Also, CD23 transcription was increased in a p38 MAPK-dependent manner and resulted in an increased level of soluble CD23 (sCD23). The β2AR-induced increase in sCD23 was associated with IgE up-regulation and possibly interacted with CD21/CD19. Using B cells from respective knockout mice, data showed that the β2AR-induced increase in IgE depended on B cell expression of CD23, CD21, and CD19. These findings suggest that at least one mechanism by which endogenous B cell activity in vivo is regulated by NE involves stimulation of the β2AR on the B cell alone to increase the level of IgE produced in a p38 MAPK- and sCD23-dependent manner.

CD86 Regulates IgG1 Production via a CD19-Dependent Mechanism

“…2D). This latter finding was also true for CD40/IL-4-activated B cells that made IgE (38). Another possible explanation is that proliferation results may be misleading when interpreting Ab results.…”

Autonomic innervation and regulation of the immune system (1987–2007)

“…However, in contrast to the β 2 AR-induced increase in IgG1 that was found to be dependent on CREB activation, the increase in IgE was not. In the case of IgE, the findings suggested that the link between β 2 AR stimulation and the increase in IgE involves the activation of p38 MAPK and formation of sCD23 (Pongratz et al, 2006). Thus, β 2 AR stimulation on a B cell that is activated in the presence of IL-4 may induce the activation of two distinct signaling pathways in a B cell to regulate the level of IgG1 and IgE produced, and also appears to upregulate CD86 expression on a B cell to participate in mediating the antibody increase.…”

Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes

“…In a B cell, p38 MAPK is activated following CD40 (10,48), B-cell receptor (48,49), and interleukin 4 (IL-4) receptor stimulation (6), as well as lipopolysaccharide treatment (12), to mediate changes in proliferation and gene expression. Recently data from our laboratory showed that ␤ 2 -adrenergic receptor (␤ 2 AR) stimulation on an activated B cell increased the level of p38 MAPK phosphorylation to regulate the level of immunoglobulin E (IgE) produced but not the level of IgG 1 (38).…”

“…␤ 2 AR stimulation either in vivo following antigen challenge (15) or in vitro at the time of B-cell activation by CD40L and IL-4 results in increased expression of CD86 on the B-cell surface (14), soluble CD23 production (38), and levels of IgE (14,38), IgG 1 (14,37), and IgM (16,40). The molecular mechanism responsible for the increased levels of IgG 1 and IgE produced by CD40L/IL-4-activated B cells exposed to norepinephrine or a ␤ 2 AR agonist was due to an increase in the rate of mature mRNA transcription, as determined by nuclear run-on analysis, without an effect on class switch recombination (36,38). The ␤ 2 AR-induced increase in IgG 1 was mediated by protein kinase A (PKA)-dependent phosphorylation of the transcription factor CREB, which translocated to the nucleus to increase the level of the transcriptional coactivator OCA-B, which resulted in increased binding of the OCA-B/ Oct-2 complex to the 3Ј-IgH enhancer (36).…”