Vascular endothelial growth factor is upregulated by interleukin-1beta in human vascular smooth muscle cells via the P38 mitogen-activated protein kinase pathway
Vascular endothelial growth factor is upregulated by interleukin-1beta in human vascular smooth muscle cells via the P38 mitogen-activated protein kinase pathway
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DOI：
10.1023/a:1012291524723
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发表时间：
2001-01-01
期刊：
影响因子：
9.8
通讯作者：
Ellis, Lee M.
中科院分区：
文献类型：
--
作者：
Jung, Young D.;Liu, Wenbiao;Ellis, Lee M.
肿瘤小血管由内皮细胞(ECs)和血管平滑肌细胞(VSMCs)组成。这些细胞已经被证明在新生血管形成过程中通过细胞因子信号相互通信。我们先前证明了白介素1β(IL-1β)可诱导人结肠癌细胞产生血管内皮生长因子(VEGF)。由于周细胞在EC功能调节中起作用，我们推测IL-1β可能通过旁分泌的方式诱导血管内皮细胞生长，从而介导EC存活。我们研究了IL-1β对人血管平滑肌细胞(HVSMCs)中血管内皮生长因子(VEGF)表达的影响及其可能的信号转导途径。IL-1β以时间和浓度依赖的方式诱导hVSMCs表达血管内皮生长因子，并增加血管内皮生长因子启动子活性和mRNA半衰期。IL-1β可在5min内诱导P38丝裂原活化蛋白激酶(MAPK)表达，但不能激活细胞外信号调节蛋白激酶(Erk)-1/2、c-jun氨基末端激酶(JNK)或Akt。特异性P38 MAPK抑制剂SB203580可阻断IL-1β诱导血管内皮生长因子的表达及启动子活性。经IL-1β处理的hVSMCs条件培养液可抑制内皮细胞的凋亡，这种作用可被血管内皮生长因子中和抗体部分阻断。这些结果表明，IL-1β可以诱导hVSMCs中的血管内皮生长因子，提示这种旁分泌信号通路可能部分地阻止了内皮细胞的凋亡。
Small tumor vessels are composed of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). These cells have been shown to communicate with each other via cytokine signaling during neovascularization. We previously demonstrated that interleukin-1beta (IL-1beta) leads to induction of vascular endothelial growth factor (VEGF) in human colon carcinoma cells. As pericytes play a role in regulating EC function, we hypothesized that IL-1beta may mediate EC survival by induction of VEGF in a paracrine manner. We investigated the effects of IL-1beta on VEGF expression in human VSMCs (hVSMCs) and the signal transduction pathways that may be involved. Treatment of hVSMCs with IL-1beta induced VEGF expression in a time- and concentration-dependent manner and increased both the VEGF promoter activity and the mRNA half-life. Treatment with IL-1beta induced the expression of P38 mitogen-activated protein kinase (MAPK) within 5 min but did not activate extracellular signal-regulated kinases (Erk)-1/2, c-jun amino terminal kinase (JNK), or Akt. SB203580, a specific P38 MAPK inhibitor, blocked the ability of IL-1beta to induce VEGF mRNA and promoter activity. Conditioned media from hVSMCs pretreated with IL-1beta prevented apoptosis of ECs, an effect that was partially abrogated by VEGF-neutralizing antibodies. These data demonstrate that IL-1beta may induce VEGF in hVSMCs, and suggest that this paracrine signaling pathway, may prevent, in part, apoptosis of ECs.