Effects of Preprotachykinin‐I Peptides on Hematopoietic Homeostasis: A Role for Bone Marrow Endopeptidases

Abstract

A BSTRACT : Hematopoiesis is maintained by "fine-tuned" regulation among cytokines, neuropeptides, neurotransmitters, and neurotrophic factors. (1-4) can be partly explained by the induction of suppressive cytokines (TGF-␤ , TNF-␣ , and INF-␥ ). Use of antagonists and screening of a dodecapeptide expression library determined that the effects of SP(1-4) were mediated by NK-1. These results show that PPT-I peptides and their endopeptidase-derived fragments may add to the fine-tuned regulation on hematopoiesis. Furthermore, PPT-I may be exerting autoregulation to protect hematopoietic stem cells. These studies have relevance to stem cell protection and BM transplant. Neurotransmitters, derived from PPT-I exert immune and hematopoietic regulation. PPT-I is also expressed locally in bone marrow (BM) stromal cells. PPT-I peptides induce the production of cytokines in BM cells, resulting in regulation of both committed progenitors (CFU-GM) and primitive hematopoietic progenitors (CAFC). Both types of progenitors are regulated differently by the two major PPT-I peptides, SP and NK-A. Endopeptidases, present in BM cells, can digest SP to produce SP(1-4) and SP(4-11). In this study, we investigated the hematopoietic effects of these fragments on CFU-GM and CAFC. Similar to the two major intact PPT-I peptides (SP and NK-A), we observed different hematopoietic effects by SP(1-4) and SP(4-11). Whereas SP(1-4) exerted inhibitory effects on CFU-GM and CAFC, SP(4-11) mediated stimulatory effects. Similar to NK-A, the inhibitory effects of SP

Targeted deletion of the tachykinin 4 gene (TAC4−/−) influences the early stages of B lymphocyte development

“…27,28 Whereas SP induced stimulatory factors, such as IL-3, IL-6, GM-CSF, SCF, and FLT3, NKA stimulated the induction of growth-suppressive factors, such as transforming growth factor-␤ (TGF-␤) and macrophage inflammatory protein-1␣ (MIP-1␣). 29,30 Although we show here that TAC4 is not expressed in purified LTRCs or ITRCs, TAC4 mRNA is abundant in the bone marrow as it is expressed by many hematopoietic cells. Specifically, TAC4 mRNA is expressed throughout B-cell development and can be detected in B cell "fractions A-F." Interestingly, NK-1 receptor mRNA is expressed in LTRCs but not ITRCs, which prompted us to investigate the potential influence of HK-1 on these populations.…”

“…Other tachykinin peptides, such as SP and NKA, have previously been shown to induce the release of stimulatory and growth-suppressive factors into the microenvironment, thereby indirectly influencing hematopoiesis. 29,30 Our findings on the effect of HK-1 on pro-B cells may therefore suggest a model in which HK-1, secreted by early B cells, elicits the release of growthsuppressive factors from the milieu, consequently resulting in a decrease of pro-B-cell proliferation. The exact nature of the NK receptor-expressing target cell that is involved in this feedback regulation remains to be investigated.…”

Stromal Derived Growth Factor-1α: Another Mediator in Neural-Emerging Immune System through Tac1 Expression in Bone Marrow Stromal Cells

“…SP has been reported to induce the production of cytokines with hemopoietic stimulatory effects (20) and has also been shown to enhance hemopoiesis, both at the level of granulocytic-monocytic progenitors and at the level of immature progenitors/LTC-IC cells (21). We therefore determined whether SDF-1␣, added exogenously at different levels (20, 50 and 100 ng/ml), could enhance LTC-IC proliferation.…”

G protein-coupled receptors in haematopoietic disruption

“…Another example could be demonstrated by the differences in binding affinities for one receptor when the different tachykinins are compared: NK-1 = SP ≥ NK-A [55,56]. SP and NK-A are derived from the preprotachykinin (PPT)-A gene through alternative splicing [57]. In addition to endogenous production in BM stroma, SP and NK-A, through their roles as neurotransmitters, could be released from nerve fibres within the BM [53].…”