Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1
Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1
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DOI：
10.1074/jbc.274.45.32048
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发表时间：
1999-11-05
影响因子：
4.8
通讯作者：
Staels, B
中科院分区：
文献类型：
--
作者：
Delerive, P;De Bosscher, K;Staels, B
白细胞介素-6（IL-6）是一种多效性细胞因子，其血浆水平在炎性疾病如动脉粥样硬化中升高。我们以前曾报道过过氧化物酶体增殖物激活受体α（PPAR α）配体（贝特类）降低动脉粥样硬化患者血浆中升高的IL-6浓度，并抑制IL-1刺激的人主动脉平滑肌细胞（SMC）分泌IL-6。在这里，我们表明，主动脉外植体分离自PPAR α-null小鼠显示炎症刺激，如脂多糖（LPS），如IL-6分泌增加证明了加剧的反应。此外，贝特类药物治疗可抑制LPS刺激的PPAR α野生型小鼠动脉中的IL-6 mRNA水平，但不能抑制PPAR α缺失小鼠的动脉中的IL-6 mRNA水平，这证明了PPAR α在贝特类药物作用中的作用。在人主动脉SMC中，贝特类抑制IL-1诱导的IL-6基因表达。此外，PPAR α的激活抑制c-Jun和p65诱导的人IL-6启动子的转录。由于c-Jun和p65也抑制了PPAR α介导的PPAR应答元件驱动启动子的激活，因此PPAR α与c-Jun和p65之间的转录干扰同时发生。这种转录干扰的发生不依赖于启动子环境，如通过使用PPAR α、p65和c-Jun Gal 4嵌合体的共转染实验所证明的。转录辅激活因子cAMP反应元件结合蛋白结合蛋白（CBP）的过表达并不能缓解PPAR α介导的p65和c-Jun的转录抑制，最后，谷胱甘肽S-转移酶下拉实验表明，PPAR α与c-dun，p65和CBP物理相互作用。总之，这些数据表明贝特类药物通过干扰NF-κ B和AP-1的反式激活能力（涉及与p65和c-Jun的直接蛋白质-蛋白质相互作用），抑制通过PPAR α的血管炎症反应。
Interleukin-6 (IL-6) is a pleiotropic cytokine, whose plasma levels are elevated in inflammatory diseases such as atherosclerosis. We have previously reported that peroxisome proliferator-activated receptor alpha (PPAR alpha) Ligands (fibrates) lower elevated plasma concentrations of IL-6 in patients with atherosclerosis and inhibit IL-1-stimulated IL-6 secretion by human aortic smooth muscle cells (SMC). Here, we show that aortic explants isolated from PPAR alpha-null mice display an exacerbated response to inflammatory stimuli, such as li popolysaccharide (LPS), as demonstrated by increased IL-6 secretion. Furthermore, fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas of PPAR alpha wild-type, but not of PPAR alpha-null mice, demonstrating a role for PPAR alpha in this fibrate action. in human aortic SMC, fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPAR alpha represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPAR alpha and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPAR alpha-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPAR alpha, p65, and c-Jun Gal4 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element-binding protein-binding protein (CBP) does not relieve PPAR alpha-mediated transcriptional repression of p65 and c-Jun, Finally, glutathione S-transferase pull-down experiments demonstrate that PPAR alpha physically interacts with c-dun, p65, and CBP. Altogether these data indicate that fibrates inhibit the vascular inflammatory response via PPAR alpha by interfering with the NF-kappa B and AP-1 transactivation capacity involving direct protein-protein interaction with p65 and c-Jun.