Effects of preprotachykinin-I peptides on hematopoietic homeostasis. A role for bone marrow endopeptidases.
Hematopoiesis is maintained by "fine-tuned" regulation among cytokines, neuropeptides, neurotransmitters, and neurotrophic factors. 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(1-4) can be partly explained by the induction of suppressive cytokines (TGF-beta, TNF-alpha, and INF-gamma). 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.
UMDNJ-New Jersey Medical School, 185 South Orange Ave, MSB Room E-579, Newark, NJ 07103, USA.
P
P
Gascón
J
J
Qian
D D
DD
Joshi
T
T
Teli
A
A
Haider
P
P
Rameshwar
D000328:Adult; D001853:Bone Marrow / Q000502:physiology*; D002478:Cells, Cultured; D010450:Endopeptidases / Q000502:physiology*; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D015213:Neuroimmunomodulation; D010446:Peptide Fragments / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology* / Q000502:physiology; D015320:Tachykinins / Q000494:pharmacology* / Q000502:physiology
D010446:Peptide Fragments; D011498:Protein Precursors; D015320:Tachykinins; C044206:preprotachykinin; D010450:Endopeptidases