Modulation of Hematopoietic Chemokine Effects In Vitro and In Vivo by DPP-4/CD26

Abstract

Dipeptidylpeptidase4 (DPP4)/CD26 truncates certain proteins, and this post-translational 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 down-modulates 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 multi-cytokine 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. Myelosupressive effects of chemokines with, but not without, a DPP4-truncation site were greatly enhanced in inhibitory potency by pretreating target bone marrow 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 non-myelosuppressive 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 post-translational modulating effects of DPP4 on chemokine activities, information offering additional biological insight into chemokine regulation of hematopoiesis.