Cholinergic Stress Responses Facilitate the Molecular Mechanisms Underlying Granulocytosis.

Glucocorticoid-initiated granulocytosis following trauma persists long after cortisol levels decrease, through yet unknown modulators of hematopoiesis. An intriguing candidate for such a modulatory role is the AChE-R splice variant of acetylcholinesterase. In brain and muscle a functional glucocorticoid response element (GRE) in the distal promoter of the ACHE gene induces overexpression of AChE-R following trauma. To explore the possibility that circulating and/or blood cells-associated AChE-R regulates sustained granulocytosis following stress, we employed labor and childbirth as the paradigm for acute, transient stress. In intra-partum women, increased AChE-R expression in granulocytes was observed by flow cytometry, which correlated significantly with their high cortisol levels and elevated AChE activity in plasma. In post-partum women, leukocyte counts, AChE-R positive granulocytes and AChE activity in plasma remained high for several days after cortisol levels declined. Furthermore, exposure to ARP, a synthetic peptide with the C-terminal sequence of AChE-R, promoted AChE gene expression in human CD34+ progenitors and facilitated their efficient proliferation in liquid cultures (1) in an antisense suppressible manner, supporting auto-regulatory prolongation of AChE-R expression. The intracellular interaction of the C-terminal domain of AChE-R with RACK1 and protein kinase Cε (2) supports such a mechanism. In 2 weeks cultures of CD34⁺ HPC, 2nM ARP induced granulocyte expansion and maturation. Additionally, exposure to ARP for 24 hours facilitated the production of pro-inflammatory cytokines interleukin (IL)-6, IL-10 and TNFα in adult PB MNC and enhanced the engraftment of CD34+ cells in NOD/SCID mice. We conclude that stress-induced AChE-R accumulation and consequent inflammatory reactions facilitate prolonged granulocytosis.