Neural Regulation of Hematopoiesis by the Tachykinins
The neuromodulators/neurotransmitters, substance P (SP) and neurokinin-A (NK-A) belong to the tachykinin family. Both peptides are widely distributed in the central and peripheral nervous systems. Although lymphoid organs such as the bone marrow (BM) are innervated by peptidergic fibers, non-neural sources for these peptides are possible. Specific cells (endothelial, macrophages and eosinophils) produce SP. In addition, we have found that cytokines induce SP-immunoreactivity (SP-IR) in BM stroma. Although both peptides interact with each of the three cloned NK- receptors (NK-1R, NK-2R, NK-3R), SP and NK-A exhibit preferences for NK-1R and NK-2R respectively. SP and NK-A interact with the G-protein coupled NK-like receptors on hematopoietic cells (CD34+, stroma) to regulate hematopoiesis. Our data indicate the presence of NK-1 and NK-2 like receptors, as well as subtypes of these receptors in BM cells. We have reported that SP stimulates in vitro hematopoiesis (erythroid and myeloid). Compared to SP, NK-A is less stimulatory to erythroid and inhibits myeloid colonies. The regulatory effects by the tachykinins are partly determined by the particular type of NK-Rs being stimulated. NK-1R appears to mediate a stimulatory response whereas, NK-2R inhibits hematopoiesis. Most of the effects by the tachykinins are indirect through the induction of growth factors. We have shown that SP induces IL-1, IL-3, IL-6, GM-CSF and c-kit ligand in BM cells and NK-A induces MlP-1α and TGF-ß. Our data indicate that the stroma is involved in most of the tachykinin-mediated effects through the induction of cytokines which in turn regulate the induction, expression and binding affinities of NK-R on BM cells. These studies suggest that the tachykinins can mediate a network of regulatory interactions among BM cells and, that this can lead to “fine-tuned” hematopoiesis. The results also provide evidence that in addition to being neuro-transmitters/-modulators, the tackykinins may be a link of a putative neurohematopoietic axis.
KeywordsMigration Leukemia Histamine Acetylcholine Calcitonin
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