IGF-1 increases macrophage motility via PKC/p38-dependent αvβ3-integrin inside-out signaling
IGF-1 increases macrophage motility via PKC/p38-dependent αvβ3-integrin inside-out signaling
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DOI：
10.1016/j.bbrc.2010.03.072
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发表时间：
2010-04-09
影响因子：
3.1
通讯作者：
Stawowy, Philipp
中科院分区：
文献类型：
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作者：
Furundzija, Vesna;Fritzsche, Jan;Stawowy, Philipp
胰岛素样生长因子(IGF)-1在人动脉粥样硬化的巨噬细胞中高表达，但其在巨噬细胞运动中的功能仍有待阐明。本研究的目的是研究IGF-1对巨噬细胞迁移的影响。结果迁移复选框实验表明，IGF-1诱导的THP-1/巨噬细胞的趋化性被含rgd的肽和α v β 3阻断抗体LM609抑制，但不受mmp抑制剂GM6001的影响。免疫印迹实验表明，IGF-1不影响MMPs或TIMPs的激活。然而，IGF-1诱导了α v β 3的募集，以及整合素衔接蛋白phospho-paxillin在局灶黏附位点的易位，Akt、PKC和p38 MAP-kinase特异性抑制剂的药理阻断实验表明，IGF-1依赖性的局灶黏附激酶（FAK）和paxillin的激活，进而促进了IGF-1的迁移。IGF-1/ igf - 1r介导的pi3 -激酶/PKC/p38依赖性信号通路在巨噬细胞迁移中起着至关重要的作用，与组织炎症密切相关，这涉及通过pi3 -激酶/PKC/p38依赖性信号通路激活整合素和局灶粘连形成，但不需要MMP激活(C) 2010 Elsevier Inc .版权所有
Macrophage migration is a key aspect in the initiation and progression of atherosclerosis Insulin-like growth factor (IGF)-1 is highly expressed in macrophages in human atheroma Its function in macrophage motility, however, remains to be elucidated The aim of this study was to investigate the impact of IGF-1 on macrophage migration, its signaling pathways and the involvement of integrins and/or matrix metalloproteinases (MMPs)Results Migration checker-box experiments demonstrated that IGF-1 induced chemotaxis in human THP-1/macrophages IGF-1 induced migration was inhibited by RGD-containing peptides and the alpha v beta 3-blocking antibody LM609, but was unaffected by the MMP-inhibitor GM6001 Immunoblotting demonstrated that IGF-1 did not affect the activation of MMPs or TIMPs, nor did it increase alpha v-integrin protein levels However, IGF-1 induced recruitment of alpha v beta 3, as well as trans-location of the integrin adaptor protein phospho-paxillin to focal adhesion sites Pharmacological blocking experiments with specific inhibitors of Akt, PKC and p38 MAP-kinase revealed that IGF-1-dependent activation of focal adhesion kinase (FAK) and paxillin, and consecutively IGF-1 facilitated migration, required IGF-1/IGF-1R-mediated PI3-kinase/PKC/p38-dependent integrin inside-out signalingConclusion IGF-1 plays a vital role in macrophage migration critically implicated in tissue inflammation This involves activation of integrins and focal adhesion formation via inside-out PI3-kinase/PKC/p38-dependent signaling, but does not require MMP activation (C) 2010 Elsevier Inc All rights reserved