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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2697-2706
HEMATOPOIESIS
Negative feedback on the effects of stem cell factor on
hematopoiesis is partly mediated through neutral endopeptidase
activity on substance P: a combined functional and proteomic
study
Deval D. Joshi,
Anju Dang,
Prem Yadav,
Jing Qian,
Persis S. Bandari,
Kunhua Chen,
Robert Donnelly,
Tammy Castro,
Pedro Gascon,
Ali Haider, and
Pranela Rameshwar
From the Information System and
Technology-Academic Computer Center and the Department of Pathology
and Laboratory Science, University of Medicine and Dentistry of
New Jersey-New Jersey Medical School; Department of Biological
Sciences, Rutger's University, Newark, NJ; and Ciphergen Biosystems,
Fremont, CA.
Hematopoietic regulation is a complex but dynamic process regulated
by intercellular and intracellular interactions within the bone marrow
(BM) microenvironment. Through neurokinin-1 (NK-1) and NK-2 receptors,
peptides (eg, substance P [SP]) encoded by the preprotachykinin-I
gene mediate distinct hematopoietic effects. Cytokines, associated with
hematopoietic stimulation, and SP regulate the expression of each other
in BM mesenchymal and immune cells. Neutral endopeptidase (NEP) uses SP
as a substrate to produce SP(1-4), which inhibits the proliferation of
matured myeloid progenitor. This study determines whether the
degradation of SP to SP(1-4) by endogenous NEP in BM stroma could be a
feedback on hematopoietic stimulation by stem cell factor (SCF).
SP(1-4) induced the production of transforming growth factor (TGF)-
and tumor necrosis factor- in BM stroma. TGF-
production accounted for part of the inhibitory effects by SP(1-4) on
the proliferation of early (granulocyte-macrophage colony-forming
units) and late (long-term culture-initiating cells) hematopoietic
progenitors. Enzyme-linked immunosorbent assays and/or protein-chip
arrays indicated a timeline change of SP to SP(1-4) in BM
stroma stimulated with SCF, which correlated with increase in NEP
messenger RNA. Since SP and its fragment, SP(1-4), interact with the
same receptor to mediate opposing hematopoietic effects, 2 interactive
studies were done to understand the dual responses of NK-1: (1) a
3-dimensional molecular model of NK-1 and SP and (2) screening of a
random dodecapeptide library for SP(1-4) interacting sites. The effects
of SP(1-4) on hematopoietic progenitors and the timeline change of SP
to SP(1-4), together with the 3-dimensional model, provide a partial
explanation for the feedback on the stimulatory effects of SCF and SP
on hematopoiesis.
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