title: Modulation of Hematopoietic Chemokine Effects In Vitro and In Vivo by DPP-4/CD26.
abstract: Dipeptidyl peptidase 4 (DPP4)/CD26 truncates certain proteins, and this posttranslational modification can influence their activity. Truncated (T) colony-stimulating factors (CSFs) are decreased in potency for stimulating proliferation of hematopoietic progenitor cells (HPCs). T-CXCL12, a modified chemokine, is inactive as an HPC chemotactic, survival, and enhancing factor for replating or ex-vivo expansion of HPCs. Moreover, T-CSFs and T-CXCL12 specifically downmodulates the positively acting effects of their own full-length molecule. Other chemokines have DPP4 truncation sites. In the present study, we evaluated effects of DPP4 inhibition (by Diprotin A) or gene deletion of HPC on chemokine inhibition of multicytokine-stimulated HPC, and on chemokine-enhancing effects on single CSF-stimulated HPC proliferation, as well as effects of DPP4 treatment of a number of chemokines. Myelosuppressive effects of chemokines with, but not without, a DPP4 truncation site were greatly enhanced in inhibitory potency by pretreating target bone marrow (BM) cells with Diprotin A, or by assaying their activity on dpp4/cd26(-/-) BM cells. DPP4 treatment of myelosuppressive chemokines containing a DPP4 truncation site produced a nonmyelosuppressive molecule, but one which had the capacity to block suppression by that unmodified chemokine both in vitro and in vivo. Additionally, DPP4 treatment ablated the single cytokine-stimulated HPC-enhancing activity of CCL3/MIP-1α and CCL4/MIP-1β, and blocked the enhancing activity of each unmodified molecule, in vitro and in vivo. These results highlight the functional posttranslational modulating effects of DPP4 on chemokine activities, and information offering additional biological insight into chemokine regulation of hematopoiesis.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana.
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana.
authors.forename: Maegan
authors.initials: M
authors.lastname: Capitano
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Campbell
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana.
authors.forename: Giao
authors.initials: G
authors.lastname: Hangoc
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana.
authors.forename: Scott
authors.initials: S
authors.lastname: Cooper
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D054405:Chemokine CCL3 / Q000737:chemistry / Q000502:physiology*; D054407:Chemokine CCL4 / Q000737:chemistry / Q000502:physiology*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000502:physiology*; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D059748:Proteolysis
chemical_list: C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse