Synergistic roles of platelet-derived growth factor-BB and interleukin-1β in phenotypic modulation of human aortic smooth muscle cells
Synergistic roles of platelet-derived growth factor-BB and interleukin-1β in phenotypic modulation of human aortic smooth muscle cells
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DOI：
10.1073/pnas.0510973103
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发表时间：
2006-02-21
影响因子：
11.1
通讯作者：
Chiu, JJ
中科院分区：
文献类型：
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作者：
Chen, CN;Li, YSJ;Chiu, JJ
平滑肌细胞（SMCS）的表型在健康和疾病的血管功能中起着重要作用。我们研究了生长因子（血小板衍生生长因子，PDGF-BB）和细胞因子（白细胞介素，IL-1 β）的协同作用诱导的SMC表型（从收缩到合成）的调制机制。人主动脉平滑肌细胞上生长的聚合胶原蛋白表现出高表达水平的收缩标志物（平滑肌α-肌动蛋白，肌球蛋白重链，和钙调蛋白）。PDGF-BB和IL-1 β单独使用对这些水平没有显著影响，但PDGF-BB和IL-1 β联合使用后显著降低。PDGF/IL-1 β共刺激还诱导Akt和p70核糖体S6激酶（p70 S6 K）的持续磷酸化。PDGF/IL-1 β共刺激对收缩标志物表达和Akt和p70 S6 K磷酸化的影响被磷脂酰肌醇3-激酶抑制剂wortmannin和LY 294002以及表达显性阴性Akt的腺病毒阻断，并且它们被组成性活性Akt模拟。PDGF-BB/ IL-10诱导PDGF受体（PDGFR）-β的持续磷酸化及其与IL-1受体（IL-1 R1）的结合。PDGFR-β中和抗体（AF 385）、IL-1 R1拮抗剂（IL-1 ra）以及PDGFR-β磷酸化特异性抑制剂（AG 1295）可阻断受体的这种激活和结合;这些药物还消除了PDGF-BB/IL-1 β诱导的信号传导和表型调节。PDGF-BB/IL-1 β可抑制细胞核内胶原诱导的血清反应因子DNA结合活性，该作用通过PDGFR-BB/IL-1 R1结合和磷脂酰肌醇3-激酶/Akt/p70 S6 K途径介导。我们的研究结果提供了对SMC表型从收缩型到合成型的调节机制的见解，例如，动脉粥样硬化。
The phenotype of smooth muscle cells (SMCS) plays an important role in vascular function in health and disease. We investigated the mechanism of modulation of SMC phenotype (from contractile to synthetic) induced by the synergistic action of a growth factor (platelet-derived growth factor, PDGF-BB) and a cytokine (interleukin, IL-1 beta). Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle alpha-actin, myosin heavy chain, and calponin). These levels were not significantly affected by PDGF-BB and IL-1 beta individually, but decreased markedly after the combined usage of PDGF-BB and IL-1 beta. PDGF/IL-1 beta costirinulation also induced a sustained phosphorylation of Akt and p70 ribosomal S6 kinase (p70S6K). The effects of PDGF/IL-1 beta costimulation on contractile marker expression and Akt and p70S6K phosphorylation were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 and by adenovirus expressing a dominant-negative Akt, and they were mimicked by constitutively active Akt. PDGF-BB/ IL-10 induced a sustained phosphorylation of PDGF receptor (PDGFR)-beta and its association with IL-1 receptor (IL-1R1). Such activation and association of receptors were blocked by a PDGFR-beta neutralizing antibody (AF385), an IL-1R1 antagonist (IL-1 ra), as well as a specific inhibitor of PDGFR-beta phosphorylation (AG1295); these agents also eliminated the PDGF-BB/IL-1 beta-induced signaling and phenotypic modulation. PDGF-BB/IL-1 beta inhibited the polymerized collagen-induced serum response factor DNA binding activity in the nucleus, and this effect was mediated by the PDGFR-beta/IL-1R1 association and phosphaticlylinositol 3-kinase/Akt/p70S6K pathway. Our findings provide insights into the mechanism of SMC phenotypic modulation from contractile to synthetic, e.g., in atherosclerosis.