Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis.
Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis.
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促进放疗、化疗或造血干细胞(HSC)移植后的造血恢复具有临床意义。二肽基肽酶(DPP4)可裂解多种底物，包括趋化因子基质细胞衍生因子-1(SDF-1)。在抑制DPP4增强SDF-1介导的祖细胞存活、体外细胞因子扩增和复制频率的实验过程中，我们意外地发现DPP4在调节集落刺激因子(CSF)活性方面具有更普遍的作用。DPP4在CSFS粒细胞-巨噬细胞(GM-CSF)、G-CSF、IL-3和红细胞生成素的N-末端发生裂解，活性降低。DPP4基因敲除或DPP4抑制增强了体外和体内的脑脊液活性。截短的DPP4与全长的人GM-CSF相比活性降低与受体结合亲和力、诱导GM-CSF受体寡聚化和信号传递能力的影响有关。在DPP4DP4−/−小鼠或接受口服活性DPP4抑制剂的小鼠中，放射或化疗后小鼠的造血功能得到增强。DPP4抑制在不影响HSC功能的情况下增强了小鼠的植入，暗示了这一方法的潜在临床应用。
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.
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影响因子：
4
作者：
Campbell, Timothy B.;Hangoc, Giao;Broxmeyer, Hal E.
通讯作者：
Broxmeyer, Hal E.
影响因子：
20.3
作者：
Chitteti, Brahmananda R.;Cheng, Ying-Hua;Srour, Edward F.
通讯作者：
Srour, Edward F.
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
4.8
作者：
Haman, A;Cadieux, C;Hoang, T
通讯作者：
Hoang, T
影响因子：
20.3
作者：
Broxmeyer, Hal E.;Lee, Man-Ryul;Yoder, Mervin C.
通讯作者：
Yoder, Mervin C.