Hydrolytic and nonenzymatic functions of acetylcholinesterase comodulate hemopoietic stress responses.
Glucocorticoid-initiated granulocytosis, excessive proliferation of granulocytes, persists after cortisol levels are lowered, suggesting the involvement of additional stress mediator(s). In this study, we report that the stress-induced acetylcholinesterase variant, AChE-R, and its cleavable, cell-penetrating C-terminal peptide, ARP, facilitate granulocytosis. In postdelivery patients, AChE-R-expressing granulocyte counts increased concomitantly with serum cortisol and AChE activity levels, yet persisted after cortisol had declined. Ex vivo, mononuclear cells of adult peripheral blood responded to synthetic ARP26 by overproduction of hemopoietically active proinflammatory cytokines (e.g., IL-6, IL-10, and TNF-alpha). Physiologically relevant ARP26)levels promoted AChE gene expression and induced the expansion of cultured CD34+ progenitors and granulocyte maturation more effectively than cortisol, suggesting autoregulatory prolongation of ARP effects. In vivo, transgenic mice overexpressing human AChE-R, unlike matched controls, showed enhanced expression of the myelopoietic transcription factor PU.1 and maintained a stable granulocytic state following bacterial LPS exposure. AChE-R accumulation and the consequent inflammatory consequences can thus modulate immune responses to stress stimuli.
Grisaru
Dan
D
Department of Obstetrics and Gynecology, Tel Aviv Sourasky Medical Center, Israel.
Pick
Marjorie
M
Perry
Chava
C
Sklan
Ella H
EH
Almog
Ronit
R
Goldberg
Ilan
I
Naparstek
Elizabeth
E
Lessing
Joseph B
JB
Soreq
Hermona
H
Deutsch
Varda
V
D000110:Acetylcholinesterase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000502:physiology; D006098:Granulocytes / Q000166:cytology / Q000201:enzymology*; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D015151:Immunoblotting; D016130:Immunophenotyping; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000097:blood / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000201:enzymology* / Q000503:physiopathology
D018952:Antigens, CD34; D010455:Peptides; D000110:Acetylcholinesterase; D006854:Hydrocortisone