Cholinergic status modulations in human volunteers under acute inflammation
Cholinergic Status, the total soluble circulation capacity for acetylcholine hydrolysis, was tested for putative involvement in individual variabilities of the recruitment of immune cells in response to endotoxin challenge. Young (average age 26) and elderly (average age 70) volunteers injected with either Escherichia coli endotoxin or saline on two different occasions were first designated Enhancers and Suppressors if they showed increase or decrease, respectively, in plasma acetylcholinesterase (AChE) activity 1.5 h after endotoxin administration compared to saline. Enhancers showed significant co-increases in plasma butyrylcholinesterase (BChE) and paraoxonase (PON1) activities, accompanied by rapid recovery of lymphocyte counts. Young Enhancers alone showed pronounced post-exposure increases in the pro-inflammatory cytokine interleukin-6 (IL-6), and upregulation of the normally rare, stress-induced AChE-R variant, suggesting age-associated exhaustion of the cholinergic effects on recruiting innate immune reactions to endotoxin challenge. Importantly, IL-6 injected to young volunteers or administered in vitro to primary mononuclear blood cells caused upregulation of AChE, but not BChE or PON1, excluding it from being the sole cause for this extended response. Interestingly, Suppressors but not Enhancers showed improved post-exposure working memory performance, indicating that limited cholinergic reactions may be beneficial for cognition. Our findings establish Cholinergic Status modulations as early facilitators and predictors of individual variabilities in the peripheral response to infection.
KeywordsHuman Cytokines Inflammation Acetylcholinesterase Butyrylcholinesterase Paraoxonase
The authors thank Dr. Tsafrir Mor of the University of Arizona for a highly purified recombinant human AChE-R.
This work was supported by the Deutsches Krebsforschungszentrum (DKFZ), the Israel Ministry of Science (MOS), BSF-US-Israel Binational Science Fund (2003028-01) and the Israeli Ministry of Commerce (NOPHAR) to H.S. The Centre of Inflammation and Metabolism (supported by a grant from the Danish National Research Foundation—DG 02-512-555); The Copenhagen Muscle Research Centre (supported by grants from The University of Copenhagen, The Faculties of Science and of Health Sciences at this university); The Copenhagen Hospital Corporation, The Danish National Research Foundation (Grant 504-14), the Commission of the European Communities (contract no. LSHM-CT-2004-005272 EXGENESIS).
- 4.Sklan EH, Lowenthal A, Korner M, Ritov Y, Landers DM, Rankinen T, Bouchard C, Leon AS, Rice T, Rao DC, Wilmore JH, Skinner JS, Soreq H (2004) Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study. Proc Natl Acad Sci USA 101:5512–5517PubMedCrossRefGoogle Scholar
- 6.Besedovsky HO, del Rey A (2000) The cytokine-HPA axis feed-back circuit. Z Rheumatol 59(Suppl 2):II/26–30Google Scholar
- 10.Reale M, Iarlori C, Gambi F, Feliciani C, Salone A, Toma L, DeLuca G, Salvatore M, Conti P, Gambi D (2004) Treatment with an acetylcholinesterase inhibitor in Alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines. J Neuroimmunol 148:162–171PubMedCrossRefGoogle Scholar
- 18.Goshen I, Yirmiya R (2007) The role of proinflammatory cytokines in memory processes and neural plasticity. Elsevier, AmsterdamGoogle Scholar
- 26.Wechsler D (1997) Wechsler Adult Intelligence Scale. The Psychological Corporation, San AntonioGoogle Scholar
- 30.Evron T, Geyer BC, Cherni I, Muralidharan M, Fletcher SP, Soreq H, Mor TS (2007) Plant-derived human acetylcholinesterase-R provides protection from lethal organophosphate poisoning and its chronic aftermath. FASEB J (in press).DOI 10.1096/fj.07-8112com