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- W2048589029 abstract "We reported that Dipeptidylpeptidase 4 (DPP4) truncates GM-CSF, G-CSF, IL-3, EPO and CXCL12 (Broxmeyer et al, 2012, Nature Med 18:1786). Truncated (TR)-CSFs are decreased in hematopoietic progenitor cell (HPC) stimulating activity, and TR-CXCL12/SDF-1 is inactive as an HPC chemotactic, survival or expansion factor. Moreover, TR-molecules block positively acting effects of their own full length (FL)-molecule. Many chemokines have DPP4 TR sites. To determine a role for DPP4 truncation on negatively acting cytokines, we assessed in vitro effects of FL, TR, and FL plus TR myelosuppressive CCL3/MIP-1α, CCL2/MCP-1, CXCL4/PF4, CXCL5/ENA-74, CXCL6/GCP-2, GXCL8/IL-8, CXCL9/MIG, and CXL10/IP-10, and non-myelosuppressive CCL4/MIP-1β and CCL5/RANTES on multi-cytokine stimulated HPC. Myelosuppressive XCL1/Lymphotoxin, without a DPP4 TR site, was also assessed. Myelosupressive chemokines with, but not without, a DPP4-TR site were 100-1000 fold enhanced in suppressor potency by pretreating target BM cells with Diprotin A, a DPP4 inhibitor, or by assaying activity on dpp4 -/- marrow. Non myelosuppressive chemokines remained non suppressive. DPP4-treatment of chemokines with myelosuppressive activity produced non-myelosuppressive molecules that blocked suppression by their FL-chemokine, likely through receptor interference. In vitro effects were reproduced in vivo after IV injection of FL, TR, and FL plus TR CCL3, CXCL8, and CXCL9. CCL3 is myelosuppressive for immature subsets of HPC responsive to stimulation by multiple cytokines, but CCL3 and non-myelosuppressive CCL4 enhance single cytokine (GM-CSF or M-CSF) stimulated colony formation in vitro by more mature HPC (Broxmeyer et al, 1989, JEM 170:1583; 1990, Blood 76:1110). We now show that DPP4-TR CCL3 and CCL4 lose their enhancing activity for GM-CSF and M-CSF stimulated HPC in vitro and in vivo, and TR-CCL3 and -CCL4 each block enhancement by FL CCL3 and CCL4. This highlights intricate in vitro and in vivo influences of DPP4 that should be considered when evaluating regulatory cytokine/chemokine effects and means to modulate hematopoiesis for biological and clinical insight." @default.
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- W2048589029 date "2014-08-01" @default.
- W2048589029 modified "2023-09-24" @default.
- W2048589029 title "DPP4 regulates in vitro and in vivo hematopoiesis mediated by myelosuppressive chemokines" @default.
- W2048589029 doi "https://doi.org/10.1016/j.exphem.2014.07.088" @default.
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