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. 2016 Nov 30;17(12):2009.
doi: 10.3390/ijms17122009.

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

Maria Di Bari  1 , Marcella Reale  2 , Marta Di Nicola  3 , Viviana Orlando  4 , Sabrina Galizia  5 , Italo Porfilio  6 , Erica Costantini  7 , Chiara D'Angelo  8 , Serena Ruggieri  9   10 , Stefano Biagioni  11 , Claudio Gasperini  12 , Ada Maria Tata  13
Affiliations

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

Maria Di Bari et al. Int J Mol Sci. .

Abstract

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis.

Keywords: acetylcholine; acetylcholinesterase; butyrylcholinesterase; cytokines; multiple sclerosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cholinergic marker levels in serum of RR-MS patients and HD. (A) ACh levels (pmol/mL); (B) AChE activity (mU/mL); (C) BuChE activity (mU/mL). The bars represent the standard error (p-values reported in figure are relative to comparison between groups).
Figure 2
Figure 2
Analysis by qRT-PCR of cholinergic marker expression in PBMC of RR-MS and HD. Expression of AChE (A); BuChE (B) and ChAT transcript (C) levels. Further, 18S was used as housekeeping gene. The bars represent the standard error (p-values reported in figure are relative to comparison between groups).
Figure 3
Figure 3
Expression of cholinergic markers in PBMC of RR-MS and HD. (A) A representative RT-PCR analysis of mediatophore and OCTN-1 performed in MS patients and HD; (B) densitometric analysis of the bands of OCTN-1 expressed in RR-MS and HD (n = 15); (C) densitometric analysis of the bands of mediatophore expressed in RR-MS and HD (n = 15). The bars represent the standard error (p-values reported in figure are relative to comparison between groups).
Figure 4
Figure 4
Cytokine levels in serum of RR-MS and HD. (A) IL-18 levels (pg/mL); (B) IL-12/IL-23p40 levels (pg/mL); (C) TNFα levels (pg/mL). Cytokine expression in PBMC of RR-MS and HD; (D) IL-18; (E) IL-12/IL-23p40; (F) TNFα 18S was used as housekeeping gene. The bars represent the standard error (p-values reported in figure are relative to comparison between groups).
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