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Ex vivo expansion of mature neutrophils from hematopoietic progenitor cells and cytokine-mediated signal transduction

造血祖细胞成熟中性粒细胞的离体扩增和细胞因子介导的信号转导

基本信息

批准号：
14570992
负责人：
HINO Masayuki
金额：
$ 1.86万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570992/
关键词：
hematopoietic progenitor cell neutrophil G-CSF TPO MAPkinase STAT IAP JAK サイトカインシグナル伝達アポトーシス JAK-STAT

项目摘要

In CD34 positive hematopoietic progenitor cells, stem cell factor(SCF), granulocyte colony-stimulating factor(G-CSF), thrombopoietin(TPO), granulocyte-macrophage colony-stimulating factor(GM-CSF), interleukin(IL)-3, and tumor necrosis factor(TNF)-α mediated phosphorylation of extracellular-signal regulated kinase(ERK), IL-1 and TNF-α mediated phosphorylation of p38 MAP kinase, TNF-α mediated phosphorylation of c-Jun N-terminal kinase (JNK). Inhibitors of p38 MAP kinase inhibited expression of CD11b and CD15 induced by IL-1b. IL-6/sIL-6R,G-CSF,TPO,GM-CSF,IL-3,IFN-α, and IFN-γ mediated phosphorylation of signal transducer and activator of transcription(STAT)3-Y,SCF,IL-6/sIL-6R,G-CSF,TPO,GM-CSF,IL-3, and TNF-α mediated phosphorylation of STST3-S,G-CSF,TPO,GM-CSF, IL-3, and IFN-a mediated phosphorylation of STST5a,G-CSF,GM-CSF,IL-3,IFN-α, and IFN-γ mediated phosphorylation of STAT5b, and IFN-α and IFN-γ mediated phosphorylation of STAT 1.Mature human neutrophils with normal functions (chemotaxis, phagocytosis and superoxide release) were ex vivo expanded from haematopoietic progenitor cells as the following procedure. CD34 positive haematopoietic progenitor cells were cultivated with SCF,IL-3,GM-CSF, and G-CSF for 7 days, and thereafter non-adherent cells were further cultivated for 7 days with G-CSF alone. TPO stimulated ex vivo expansion of mature neutrophils in the early stages of differentiation. Human neutrophils were expressed members of the inhibitor of apoptosis (LAP) family (cIAP1,cIAP2, and X-linked LAP). G-CSF selectively up-regulated c-IAP2 expression. A specific inhibitor of Janus kinase 2(JAK2) inhibited G-CSF-induced up-regulation of cIAP2, phosphorylation of STAT3, and the antiapoptotic effects. In monocyte, G-CSF inhibited LPS-induced TNF-α production and activated STST3. These effects were prevented by an inhibitor of JAK2.

在CD34阳性造血祖细胞中，干细胞因子（SCF）、粒细胞集落刺激因子（G-CSF）、血小板生成素（TPO）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、白细胞介素(IL)-3和肿瘤坏死因子(TNF)-α介导的细胞外信号调节激酶（ERK）磷酸化，IL-1和TNF-α介导的p38 MAP激酶磷酸化，TNF-α介导的c-Jun n -末端激酶（JNK）磷酸化。p38 MAP激酶抑制剂抑制IL-1b诱导的CD11b和CD15的表达。il - 6 / sIL-6R, g - csf,传真照片,gm - csf IL-3,干扰素-α和干扰素-γ介导的磷酸化信号传感器和激活的转录(STAT)仍自洽场,il - 6 / sIL-6R, g - csf,传真照片,gm - csf, IL-3,和肿瘤坏死因子-α介导的磷酸化STST3-S, g - csf,传真照片,gm - csf, IL-3, STST5a IFN-a介导的磷酸化,g - csf, gm - csf, IL-3,干扰素-α干扰素-γ介导的磷酸化STAT5b和干扰素-α和干扰素-γ介导的磷酸化统计1。成熟的人中性粒细胞具有正常功能（趋化、吞噬和超氧化物释放），从造血祖细胞体外扩增。将CD34阳性造血祖细胞与SCF、IL-3、GM-CSF和G-CSF共同培养7天，然后将非贴壁细胞与G-CSF单独培养7天。TPO刺激成熟中性粒细胞在分化早期的体外扩增。人类中性粒细胞表达凋亡抑制剂（LAP）家族成员（cIAP1、cIAP2和X-linked LAP）。G-CSF选择性上调c-IAP2的表达。Janus kinase 2（JAK2）的特异性抑制剂抑制g - csf诱导的cIAP2上调、STAT3磷酸化和抗凋亡作用。在单核细胞中，G-CSF抑制lps诱导的TNF-α产生并激活STST3。这些作用被JAK2抑制剂所阻止。