title: Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis.
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.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. hbroxmey@iupui.edu
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hoggatt
authors.forename: Heather A
authors.initials: HA
authors.lastname: O'Leary
authors.forename: Charlie
authors.initials: C
authors.lastname: Mantel
authors.forename: Brahmananda R
authors.initials: BR
authors.lastname: Chitteti
authors.forename: Scott
authors.initials: S
authors.lastname: Cooper
authors.forename: Steven
authors.initials: S
authors.lastname: Messina-Graham
authors.forename: Giao
authors.initials: G
authors.lastname: Hangoc
authors.forename: Sherif
authors.initials: S
authors.lastname: Farag
authors.forename: Sara L
authors.initials: SL
authors.lastname: Rohrabaugh
authors.forename: Xuan
authors.initials: X
authors.lastname: Ou
authors.forename: Jennifer
authors.initials: J
authors.lastname: Speth
authors.forename: Louis M
authors.initials: LM
authors.lastname: Pelus
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Campbell
mesh_terms: D000818:Animals; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D016130:Immunophenotyping; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011878:Radiotherapy / Q000009:adverse effects*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D017931:DNA Primers; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4