Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis
| Autor: | Jonathan Hoggatt, Giao Hangoc, Steven Messina-Graham, Sara L. Rohrabaugh, Sherif S. Farag, Brahmananda R. Chitteti, Louis M. Pelus, Heather O'Leary, Xuan Ou, Jennifer M. Speth, Hal E. Broxmeyer, Timothy B. Campbell, Scott Cooper, Charlie Mantel, Edward F. Srour |
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| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Drug-Related Side Effects and Adverse Reactions Dipeptidyl Peptidase 4 medicine.medical_treatment Biology Mass Spectrometry Article General Biochemistry Genetics and Molecular Biology Cell Line Immunophenotyping Mice In vivo Internal medicine medicine Animals Humans Progenitor cell DNA Primers Mice Knockout Radiotherapy Granulocyte-Macrophage Colony-Stimulating Factor Hematopoietic stem cell General Medicine Colony-stimulating factor Chemokine CXCL12 Hematopoiesis Mice Inbred C57BL Transplantation Haematopoiesis Cytokine Endocrinology medicine.anatomical_structure Cancer research Ex vivo Signal Transduction |
| Zdroj: | Nature Medicine. 18:1786-1796 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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