Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors

Abstract

Although acetylcholine (ACh) is well known for its neurotransmitter function, recent studies have indicated that it also functions as an immune cytokine that prevents macrophage activation through a 'cholinergic (nicotinic) anti-inflammatory pathway'. In this study, we used the macrophage-like U937 cells to elucidate the mechanisms of the physiologic control of cytokine production by auto/ paracrine ACh through the nicotinic class of ACh receptors (nAChRs) expressed in these cells. Stimulation of cells with lipopolysaccharide upregulated expression of α1, α4, α5, α7, α10, β1 and β3 subunits, downregulated α6 and β2 subunits, and did not alter the relative quantity of α9 and β4 mRNAs. Distinct nAChR subtypes showed differential regulation of the production of pro-and antiinflammatory cytokines. While inhibition of the expression of the TNF-α gene was mediated predominantly by the α-bungarotoxin sensitive nAChRs, that of the IL-6 and IL-18 genes-by the mecamylamine-sensitive nAChRs. Both the Mec-and αBtx-sensitive nAChRs regulated expression of the IL-1β gene equally efficiently. Upregulation of IL-10 production by auto/paracrine ACh was mediated predominantly through α7 nAChR. These findings offer a new insight on how nicotinic agonists control inflammation, thus laying a groundwork for the development of novel immunomodulatory therapies based on the nAChR subtype selectivity of nicotinic agonists.

Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release

“…These results suggested the involvement of CHRNA7 homomers or receptors containing CHRNA9 (21,22). In agreement with the results published by Chernyavsky et al (23), mRNAs for CHRNA7, CHRNA9, and CHRNA10 were detected in unprimed and LPS-primed U937 cells. In addition, the inactive duplicate CHRFAM7A was readily detectable (Supplemental Fig.…”

The antishock effect of anisodamine requires the upregulation of α7 nicotine acetylcholine receptors by IL-10

“…However, the molecular mechanisms and physiological and pathological significance of these regulations remain to be further explored. Consistent with our findings in RAW264.7 macrophage cells, it was shown recently that LPS upregulates the expression of α7 nAChRs in macrophage-like U937 cells (Chernyavsky et al, 2010). Given the role of this receptor in the mediation of the cholinergic anti-inflammatory action in sepsis, it is conceivable that an LPS-induced upregulation of α7 nAChRs represents a negative feedback that modulates the inflammatory reaction triggered by LPS.…”

Some Aspects of the Normal Role of Neuromodulators in the Immune System

“…The cholinergic anti-inflammatory pathway, which acts through the macrophage α7-nicotinic acetylcholine receptor (α7nAChR), is important in innate immunity, in obesity-induced inflammation and insulin resistance [50]. Up-regulation of IL-10 production by auto/paracrine ACh is mediated predominantly through alpha7 nAChR [51]. Monocytes have nicotinic ACh receptors that are involved in the synthesis of C2, the second component of complement [52].…”