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Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis.
- Source :
-
Nature medicine [Nat Med] 2012 Dec; Vol. 18 (12), pp. 1786-96. Date of Electronic Publication: 2012 Nov 18. - Publication Year :
- 2012
-
Abstract
- Enhancement of hematopoietic recovery after radiation, chemotherapy, or hematopoietic stem cell (HSC) transplantation is clinically relevant. Dipeptidylpeptidase (DPP4) cleaves a wide variety of substrates, including the chemokine stromal cell-derived factor-1 (SDF-1). In the course of experiments showing that inhibition of DPP4 enhances SDF-1-mediated progenitor cell survival, ex vivo cytokine expansion and replating frequency, we unexpectedly found that DPP4 has a more general role in regulating colony-stimulating factor (CSF) activity. DPP4 cleaved within the N-termini of the CSFs granulocyte-macrophage (GM)-CSF, G-CSF, interleukin-3 (IL-3) and erythropoietin and decreased their activity. Dpp4 knockout or DPP4 inhibition enhanced CSF activities both in vitro and in vivo. The reduced activity of DPP4-truncated versus full-length human GM-CSF was mechanistically linked to effects on receptor-binding affinity, induction of GM-CSF receptor oligomerization and signaling capacity. Hematopoiesis in mice after radiation or chemotherapy was enhanced in Dpp4(-/-) mice or mice receiving an orally active DPP4 inhibitor. DPP4 inhibition enhanced engraftment in mice without compromising HSC function, suggesting the potential clinical utility of this approach.
- Subjects :
- Animals
Cell Line
DNA Primers genetics
Dipeptidyl Peptidase 4 genetics
Hematopoiesis drug effects
Hematopoiesis radiation effects
Humans
Immunophenotyping
Mass Spectrometry
Mice
Mice, Inbred C57BL
Mice, Knockout
Signal Transduction genetics
Chemokine CXCL12 metabolism
Dipeptidyl Peptidase 4 metabolism
Drug-Related Side Effects and Adverse Reactions
Granulocyte-Macrophage Colony-Stimulating Factor metabolism
Hematopoiesis physiology
Radiotherapy adverse effects
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 18
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 23160239
- Full Text :
- https://doi.org/10.1038/nm.2991