Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells -: Role of Gab1 and MEKK3 in TNF-α-induced c-Jun and NF-κB activation and adhesion molecule expression
Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells -: Role of Gab1 and MEKK3 in TNF-α-induced c-Jun and NF-κB activation and adhesion molecule expression
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DOI：
10.1161/01.res.0000021127.83364.7d
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发表时间：
2002-06-14
影响因子：
20.1
通讯作者：
Abe, J
中科院分区：
文献类型：
--
作者：
Che, WY;Lerner-Marmarosh, N;Abe, J
胰岛素样生长因子(IGF)-1和I型IGF-1受体是血管功能的重要调节因子，可能与心血管疾病有关。我们假设IGF-1通过增强促炎细胞因子信号转导导致内皮细胞功能障碍以及中性粒细胞和单核细胞粘附分子的表达。长期使用IGF-1处理内皮细胞可增强c-Jun和核因子NF-kappaB被肿瘤坏死因子(TNF)- α激活，并增强TNF- α介导的粘附分子表达。在IGF-1的作用下，c-Jun/c-Jun nh2末端激酶信号通路中激酶（MEKK1、MEK4和JNK1/2）的表达没有变化，但胰岛素受体底物-1和grb2相关结合物-1 （Gab]）的表达显著降低。由于Gab1参与了tnf - α对c-Jun和NF-kappaB的激活，因此我们重点研究了Gab1依赖性信号。Gab1抑制tnf - α对c-Jun和NF-kappaB的转录激活。有趣的是，Gab1抑制MEKK3诱导的c-Jun转录活性，而不抑制MEKK1和MEK4。Gab1与MEKK3相关，MEKK3的催化失活形式抑制tnf - α诱导的c-Jun和NF-kappaB转录激活，表明Gab1和MEKK3在tnf - α信号传导中起关键作用。这些数据表明，Gab1和MEKK3通过调节c-Jun和NF-kappaB的激活在内皮细胞炎症中发挥重要作用。此外，igf -1介导的Gab1表达下调代表了促进血管炎症和动脉粥样硬化的新机制。
Insulin-like growth factor (IGF)-1 and the type I IGF-1 receptor are important regulators of vascular function that may contribute to cardiovascular disease. We hypothesized that IGF-1 causes endothelial cell dysfunction and expression of neutrophil and monocyte adhesion molecules by enhancing pro-inflammatory cytokine signal transduction. Long-term IGF-1 treatment of endothelial cells potentiated c-Jun and nuclear factor NF-kappaB activation by tumor necrosis factor (TNF)-alpha and enhanced TNF-alpha-mediated adhesion molecule expression. In response to IGF-1 treatment, the expression of kinases in the c-Jun/c-Jun NH2-terminal kinase signaling pathway (MEKK1, MEK4, and JNK1/2) was unchanged, but expressions of insulin receptor substrate-1 and Grb2-associated binder-1 (Gab]) were significantly decreased. Because Gab1 is involved in both c-Jun and NF-kappaB activation by TNF-alpha, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-kappaB transcriptional activation by TNF-alpha. Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-alpha-induced c-Jun and NF-kappaB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-alpha signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-kappaB. Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.