Muscarinic Acetylcholine Receptors Modulate Interleukin-6 Production and Immunoglobulin Class Switching in Daudi Cells

Abstract

B cells express muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs, respectively). Following immunization with ovalbumin, serum immunoglobulin G (IgG) and interleukin (IL)-6 levels were lower in M 1 and M 5 mAChR double-deficient mice and higher in α7 nAChR-deficient mice than in wild-type mice. This suggests mAChRs participate in the cytokine production involved in B cell differentiation into plasma cells, which induces immunoglobulin class switching from IgM to IgG. However, because these results were obtained with conventional knockout mice, in which all cells in the body were affected, the specific roles of these receptors expressed in B cells remains unclear. In the present study, Daudi B lymphoblast cells were used to investigate the specific roles of mAChRs and nAChR in B cells. Stimulating Daudi cells using Pansorbin cells (heat-killed, formalin-fixed Staphylococcus aureus coated with protein A) upregulated expression of M 1-M 4 mAChRs and the α4 nAChR subunit. Under these conditions, mAChRs, but not nAChRs, mediated immunoglobulin class switching to IgG. This effect was blocked by scopolamine, a non-selective mAChR antagonist, and 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a G q/11-coupled M 1 , M 3 , M 5 antagonist. In addition, IL-6 secretion was further enhanced following mAChR activation. Thus, G q/11-coupled mAChRs expressed in B cells thus appear to contribute to IL-6 production and B cell maturation into IgG-producing plasma cells.

Regulation of Immune Functions by Non-Neuronal Acetylcholine (ACh) via Muscarinic and Nicotinic ACh Receptors

“…In addition to nAChRs [84], B cells express all five mAChR subtypes (M 1 -M 5 ) [2,3,85]. Oxo-M stimulation of mAChRs on Daudi human B-cell leukemia cells induces an increase in [Ca 2+ ] i and Ca 2+ oscillations mediated by Ca 2+ release from intracellular Ca 2+ stores [47,48,61].…”

“…Oxo-M stimulation of mAChRs on Daudi human B-cell leukemia cells induces an increase in [Ca 2+ ] i and Ca 2+ oscillations mediated by Ca 2+ release from intracellular Ca 2+ stores [47,48,61]. Expression of mAChRs on B cells appears to be modulated by activation elicited by immune stimuli [85]. For instance, Pansorbin ® , which are heat-killed and fixed Staphylococcus aureus with a coat of protein A, trigger Th cell-independent activation of toll-like receptor (TLR) 2 on B cells, leading to mitogenic responses [86].…”

“…For instance, Pansorbin ® , which are heat-killed and fixed Staphylococcus aureus with a coat of protein A, trigger Th cell-independent activation of toll-like receptor (TLR) 2 on B cells, leading to mitogenic responses [86]. Additionally, in Daudi cells, 24-h exposure to Pansorbin ® results in up-regulated expression of the genes encoding the M 1 -M 4 mAChRs and the α4nAChR subunit [85]. Similarly, PMA, a PKC activator, plus ionomycin, a calcium ionophore, up-regulate mRNA expression of both M 3 and M 5 mAChRs in CCRF-CEM and Daudi cells [87].…”

Cholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity

“…abolishes mAChR-mediated immunoglobulin class switching to IgG in B cells. It inhibits the production of IL-6 and the maturation of B cells into IgG-producing plasma cells(245). M 3 mAChR-mediated IL-8 expression in regulating inflammatory response via PKC/NF-kB signaling axis is completely antagonized by 4-DAMP(246).…”