αVβ3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-κB activation.
αVβ3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-κB activation.
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DOI：
10.1002/jcp.22356
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发表时间：
2011-02
影响因子：
5.6
通讯作者：
Verin, Alexander D.
中科院分区：
文献类型：
--
作者：
Antonov, Alexander S.;Antonova, Galina N.;Munn, David H.;Mivechi, Nahid;Lucas, Rudolf;Catravas, John D.;Verin, Alexander D.
控制巨噬细胞对致病性刺激的反应对于预防和恢复与许多疾病发病机制相关的炎症状态至关重要。粘附受体αVβ3整合素被认为是调节巨噬细胞分化和巨噬细胞对外部信号反应的重要受体，但它在巨噬细胞相关炎症中的作用尚未被证实。通过人血液单核细胞（Mo）和单核细胞源性巨噬细胞（MDMs）的体外模型，我们证明αVβ3连接导致转录因子NF-κB dna结合活性持续增加，与对照同型匹配的IgG1相比。在从个体供体分离的MDMs中，NF-κ b的激活与NF-κ b依赖性促炎细胞因子mRNA表达的增加平行，例如TNF-α（8- 28倍），IL-1β（15- 30倍），IL-6（2- 4倍）和IL-8（5- 15倍），而IL-10 mRNA水平下降超过10倍。在αVβ3受体结扎后，TNF-α (10 ng/ml)或LPS （200 ng/ml, 1000 EU）处理可增强NF-κB和LPS诱导的TNF-α分泌的协同激活。作为对照，αVβ3整合素抑制剂环RGD （10 μg/ml, IC50 = 7.6 μM）可减弱αVβ3的结扎作用，αVβ3整合素的天然配体vitronectin可通过固定抗αVβ3整合素单抗再现αVβ3的活化作用。我们推测αVβ3的激活可以维持病理状态下的慢性炎症过程，αVβ3结联的缺失可以使巨噬细胞脱离炎症状态。
Controlling macrophage responses to pathogenic stimuli is critical for prevention of and recovery from the inflammatory state associated with the pathogenesis of many diseases. The adhesion receptor αVβ3 integrin is thought to be an important receptor that regulates macrophage differentiation and macrophage responses to external signaling, but it has not been previously identified as a contributor to macrophage-related inflammation. Using an in vitro model of human blood monocytes (Mo) and monocyte-derived macrophages (MDMs) we demonstrate that αVβ3 ligation results in sustained increases of the transcription factor NF-κB DNA-binding activity, as compared with control isotype-matched IgG1. Activation of NF-κB parallels the increase of NF-κB-dependent pro-inflammatory cytokine mRNA expression in MDMs isolated from individual donors, for example, TNF-α (8- to 28-fold), IL-1β (15- to 30-fold), IL-6 (2- to 4-fold), and IL-8 (5- to 15-fold) whereas there is more than a 10-fold decrease in IL-10 mRNA level occurs. Upon ligation of the αVβ3 receptor, treatment with TNF-α (10 ng/ml) or LPS (200 ng/ml, 1,000 EU) results in the enhanced and synergistic activation of NF-κB and LPS-induced TNF-α secretion. As additional controls, an inhibitor of αVβ3 integrin, cyclic RGD (10 μg/ml; IC50 = 7.6 μM), attenuates the effects of αVβ3 ligation, and the natural ligand of αVβ3 integrin, vitronectin, reproduces the effects of αVβ3 activation by an immobilizing anti-αVβ3 integrin mAb. We hypothesize that αVβ3 activation can maintain chronic inflammatory processes in pathological conditions and that the loss of αVβ3 ligation will allow macrophages to escape from the inflammatory state.
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影响因子：
6
作者：
Bedke, Jens;Kiss, Eva;Groene, Hermann-Josef
通讯作者：
Groene, Hermann-Josef
影响因子：
8
作者：
McCabe, N. P.;De, S.;Byzova, T. V.
通讯作者：
Byzova, T. V.
DOI：
10.1083/jcb.143.7.2081
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Byzova TV;Plow EF
通讯作者：
Plow EF
DOI：
10.1164/ajrccm.162.3.9906129
发表时间：
2000-09-01
影响因子：
24.7
作者：
Blackwell, TS;Yull, FE;Kerr, LD
通讯作者：
Kerr, LD
影响因子：
6
作者：
Antonov, AS;Kolodgie, FD;Gerrity, RG
通讯作者：
Gerrity, RG