Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Nat Med. 2012 Dec;18(12):1786-96. doi: 10.1038/nm.2991. Epub 2012 Nov 18.
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.
增强辐射、化疗或造血干细胞（HSC）移植后的造血恢复在临床上具有重要意义。二肽基肽酶（DPP4）可切割多种底物，包括趋化因子基质细胞衍生因子-1（SDF-1）。在实验中，我们发现抑制 DPP4 可增强 SDF-1 介导的祖细胞存活、体外细胞因子扩增和再种植频率，出乎意料的是，我们发现 DPP4 在调节集落刺激因子（CSF）活性方面具有更普遍的作用。DPP4 可在 CSF 的 N 端切割粒细胞-巨噬细胞（GM）-CSF、G-CSF、白细胞介素-3（IL-3）和促红细胞生成素，并降低其活性。Dpp4 敲除或 DPP4 抑制可增强 CSF 在体外和体内的活性。与全长人 GM-CSF 相比，DPP4 截断的 GM-CSF 活性降低与受体结合亲和力、GM-CSF 受体寡聚化和信号转导能力的影响有关。Dpp4(-/-) 小鼠或接受口服 DPP4 抑制剂的小鼠在辐射或化疗后造血增强。DPP4 抑制可增强移植后造血，而不影响 HSC 功能，提示该方法具有潜在的临床应用价值。
