Inhibitory effect of the substance P and its derivative on erythropoietin-independent growth of erythroid progenitors in polycythemia vera.
Regulation of normal hematopoiesis by neuropeptide substance P (SP) and its amino terminal fragment, SP(1-4), has been reported. Endogenous erythroid colony (EEC) formation without erythropoietin is characteristic of polycythemia vera (PV), a chronic myeloproliferative disorder. We investigated the effect(s) of SP and SP(1-4) on EEC formation from PV BM mononuclear cells (BMMCs) and purified CD36+ erythroid progenitors. We found a potent in vitro inhibitory effect of SP and SP(1-4) on PV EEC formation for both BMMCs and CD36+ erythroid progenitors. The influence of SP and SP(1-4) on PV progenitor erythroid differentiation and cell viability was also investigated, and the impact of neurokinin receptors and G proteins in the inhibition were analyzed by quantitative PCR and with specific inhibitors. This progenitor inhibition was: (1) not mediated by accessory cells; (2) characterized by an increase in cell death and inhibition of the EPOindependent terminal erythroid differentiation; and (3) not mediated by the same neurokinin receptor. NK-1R and NK-2R antagonists completely abrogated the SP inhibitory effect but not SP(1-4)-induced inhibition. Furthermore, the truncated form of the NK-1R was predominant over the full-length mRNA and could mediated the SP inhibitory effect on PV CD36+ erythroid progenitors. Different G proteins were also implicated according to the erythroid differentiation stage of the PV cells. The observation of an inhibitory effect of SP and its related peptide, SP(1-4), on PV EEC formation at physiological concentrations (10-8M) suggests that neuropeptides represent a way to downregulate pathologic expansion of PV progenitors.
Le Gall
Christelle
C
Laboratoire de Thérapie Cellulaire et d'Immuno-Biologie du Cancer, EA 2216-CHU de Brest-Hôpital Morvan, 29609 Brest, France. christelle_legall@hotmail.com
Ianotto
Jean-Christophe
JC
Hardy
Elisabeth
E
Ugo
Valérie
V
Eveillard
Jean-Richard
JR
Ngo-Sack
Françoise
F
Bourquard
Pascal
P
Morice
Patrick
P
Berthou
Christian
C
D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000502:physiology; D004921:Erythropoietin / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D011087:Polycythemia Vera / Q000097:blood / Q000188:drug therapy*; D012333:RNA, Messenger / Q000032:analysis; D018039:Receptors, Tachykinin / Q000235:genetics; D013373:Substance P / Q000494:pharmacology*
D010446:Peptide Fragments; D012333:RNA, Messenger; D018039:Receptors, Tachykinin; D004921:Erythropoietin; D013373:Substance P; C042612:substance P (1-4); D019204:GTP-Binding Proteins