title: 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.
abstract: 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)-beta and tumor necrosis factor-alpha in BM stroma. TGF-beta 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.
authors.affiliation: 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, Newark, NJ 07103, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Joshi
authors.forename: A
authors.initials: A
authors.lastname: Dang
authors.forename: P
authors.initials: P
authors.lastname: Yadav
authors.forename: J
authors.initials: J
authors.lastname: Qian
authors.forename: P S
authors.initials: PS
authors.lastname: Bandari
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Donnelly
authors.forename: T
authors.initials: T
authors.lastname: Castro
authors.forename: P
authors.initials: P
authors.lastname: Gascon
authors.forename: A
authors.initials: A
authors.lastname: Haider
authors.forename: P
authors.initials: P
authors.lastname: Rameshwar
mesh_terms: D001665:Binding Sites; D001854:Bone Marrow Cells; D000070819:Discoidin Domain Receptor 1; D025461:Feedback, Physiological; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins; D008958:Models, Molecular; D015260:Neprilysin / Q000378:metabolism* / Q000494:pharmacology; D019151:Peptide Library; D012333:RNA, Messenger / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology* / Q000502:physiology; D013373:Substance P / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D019151:Peptide Library; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D013373:Substance P; C083249:Ddr1 protein, mouse; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D015260:Neprilysin