Hydrolytic and nonenzymatic functions of acetylcholinesterase comodulate hemopoietic stress responses

Dan Grisaru, Marjorie Pick, Chava Perry, Ella H. Sklan, Ronit Almog, Ilan Goldberg, Elizabeth Naparstek, Joseph B. Lessing, Hermona Soreq, Varda Deutsch

Research output: Contribution to journalArticlepeer-review

Abstract

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-α). 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.

Original languageEnglish
Pages (from-to)27-35
Number of pages9
JournalJournal of Immunology
Volume176
Issue number1
DOIs
StatePublished - 1 Jan 2006

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