Interleukin-1β inhibits expression of p21(WAF1/CIP1) and p27(KIP1) and enhances proliferation in response to platelet-derived growth factor-BB in smooth muscle cells
Interleukin-1β inhibits expression of p21(WAF1/CIP1) and p27(KIP1) and enhances proliferation in response to platelet-derived growth factor-BB in smooth muscle cells
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DOI：
10.1161/01.atv.0000023428.69244.49
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发表时间：
2002-08-01
影响因子：
8.7
通讯作者：
Daum, G
中科院分区：
文献类型：
--
作者：
Nathe, TJ;Deou, J;Daum, G
血管内膜生长依赖于平滑肌细胞（SMC）的迁移和增殖，并受血管损伤的血栓形成和炎症反应的调节。血小板衍生生长因子（PDGF）-BB和白细胞介素（IL）-1 β已被证明有助于动脉粥样硬化的内膜增生和病变进展。IL-1对SMC的促有丝分裂作用已被报道，并已被归因于PDGF-A链的表达。在一些但不是所有的研究中，发现IL-1 β与生长因子（包括PDGF）合作刺激增殖。这种合作效应的分子基础是未知的，是本study.Methods和Results-We的主题证明，在狒狒主动脉SMCs，IL-1 β增强PDGF-BB独立的PDGF-A信号诱导的增殖。IL-1 β增加视网膜母细胞瘤蛋白的磷酸化，这是细胞周期中G（1）向S转变的关键步骤。对细胞周期蛋白和细胞周期蛋白依赖性激酶（CDK）抑制剂表达水平的分析表明，IL-1 β通过下调p21和p27刺激CDK。与这一假设相一致的是，发现PDGF-BB诱导的CDK 2活性在IL-1 β存在下增强2.3+/-0.2倍。结论-我们的数据表明，IL-1 β可能通过抑制PDGF-BB诱导的p21和p27促进血管损伤后SMC增殖和动脉粥样硬化形成。
Objective-Intimal growth depends on smooth muscle cell (SMC) migration and proliferation and is regulated by thrombotic and inflammatory responses to vascular injury. Platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1beta have been shown to contribute to intimal hyperplasia and lesion progression in atherosclerosis. Mitogenic effects of IL-1 on SMCs have been reported and have been attributed to the expression of PDGF-A chain. In some, but not all, studies, IL-1beta was found to cooperate with growth factors, including PDGF, in stimulating proliferation. The molecular basis for such cooperative effects is unknown and is the subject of the present study.Methods and Results-We demonstrate that in baboon aortic SMCs, IL-1beta enhances the proliferation induced by PDGF-BB independently of PDGF-A signaling. IL-1beta increases the phosphorylation of retinoblastoma protein, a pivotal step in the G(1)-to-S transition in the cell cycle. Analysis of expression levels of cyclins and cyclin-dependent kinase (CDK) inhibitors suggests that IL-1beta stimulates CDKs by downregulating p21 and p27. Consistent with this hypothesis is the finding that CDK2 activity, induced by PDGF-BB, is enhanced 2.3+/-0.2-fold in the presence of IL-1beta.Conclusions-Our data suggest that IL-1beta may promote SMC proliferation after vascular injury and in atherogenesis by suppression of PDGF-BB-induced p21 and p27.