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Intracellular signaling mechanisms in normal human hematopoietic progenitors and mature leukocytes

正常人造血祖细胞和成熟白细胞的细胞内信号传导机制

基本信息

批准号：
15390304
负责人：
KITAGAWA Seiichi
金额：
$ 7.74万
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 (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390304/
关键词：
Neutrophil Monocyte G-CSF GM-CSF TNF-α MAP kinase Apoptosis STAT3 インターフェロン clAP2 運動性 cIAP2 STAT3α STAT3γ エラスターゼ TNFα LPS

项目摘要

1.Regulation of actin reorganization and motility in human neutrophils by cytokines : Stimulation of neutrophils with G-CSF, GM-CSF or TNF-α resulted in actin de polymerization and morphological change. The maximum responses were detected within 20 min. We found that activation of ERK and p38 MAPK plays a critical role in actin reorganization and morphological change induced by these cytokines. G-CSF also induced random migration in neutrophils, and G-CSF-induced neutrophil migration was regulated by ERK and P13K.2.Regulation of human monocyte functions by G-CSF : Among the signaling molecules, STAT3 was selectively activated in monocytes stimulated by G-CSF. We found that G-CSF inhibited LPS-induced TNF-α production in monocytes through activation of STAT3. The immunomodulation observed in vivo by G-CSF administration may be partly ascribed to the direct effect of G-CSF on monocyte functions.3.Human neutrophil survival and cIAP2 : Human neutrophils were found to express members of the inhibitor of apoptosis (IAP) family, namely cIAP1, cIAP2 and XIAP. Among these members, cIAP2 expression was selectively up-regulated by G-CSF stimulation in vitro and in vivo. Up-regulation of cIAP2 expression was mediated by activation of the JAK2-STAT3 pathway. Increased expression of cIAP2 protein may contribute to G-CSF-mediated anti-apoptotic effect on neutrophils. In addition, we found that mature neutrophils from a patient with chronic neutrophilic leukemia exhibited remarkable over-expression of cIAP2 mRNA and prolongation of survival.4.STAT3 isoforms expressed in human neutrophils : It has been reported that STAT3γ is a major STAT3 isoform in human neutrophils. We found that, in contrast to the previous reports, STAT3α, but not STAT3γ, was primarily expressed in human neutrophils, and STAT3γ was rapidly generated from STAT3α by limited proteolysis with granule-derived serine proteases during preparation of neutrophil lysates with the conventional lysis buffer.

1.细胞因子对人中性粒细胞中肌动蛋白重组和运动的调节：用G-CSF、GM-CSF或TNF-α刺激中性粒细胞导致肌动蛋白解聚和形态学改变。我们发现，ERK和p38 MAPK的激活在这些细胞因子诱导的肌动蛋白重组和形态学变化中起着至关重要的作用。G-CSF还能诱导中性粒细胞的随机迁移，并且G-CSF诱导的中性粒细胞迁移受ERK和P13 K的调节。2. G-CSF对人单核细胞功能的调节：在G-CSF刺激的单核细胞中，STAT 3被选择性激活。我们发现G-CSF通过激活STAT 3抑制LPS诱导的单核细胞TNF-α的产生。G-CSF对单核细胞功能的直接影响可能是G-CSF体内免疫调节作用的部分原因。3.人中性粒细胞存活率和cIAP 2：人中性粒细胞表达凋亡抑制因子（IAP）家族成员cIAP 1、cIAP 2和XIAP。在这些成员中，cIAP 2表达在体外和体内通过G-CSF刺激选择性上调。cIAP 2表达的上调是通过JAK 2-STAT 3通路的激活介导的。cIAP 2蛋白表达的增加可能有助于G-CSF介导的对中性粒细胞的抗凋亡作用。此外，我们还发现慢性嗜中性粒细胞白血病患者的成熟中性粒细胞中cIAP 2 mRNA的过度表达和生存期的延长。4.中性粒细胞中STAT 3亚型的表达：已有报道，STAT 3 γ是中性粒细胞中主要的STAT 3亚型。我们发现，与以前的报道相反，STAT 3 α，而不是STAT 3 γ，主要在人中性粒细胞中表达，并且在用常规裂解缓冲液制备中性粒细胞裂解物期间，通过颗粒来源的丝氨酸蛋白酶的有限蛋白水解，STAT 3 γ由STAT 3 α快速产生。