Tumor necrosis factor-α-mediated protein kinases in regulation of scavenger receptor and foam cell formation on macrophage
Tumor necrosis factor-α-mediated protein kinases in regulation of scavenger receptor and foam cell formation on macrophage
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DOI：
10.1074/jbc.m003464200
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发表时间：
2000-12-29
影响因子：
4.8
通讯作者：
Twu, YC
中科院分区：
文献类型：
--
作者：
Hsu, HY;Twu, YC
我们之前报道过肿瘤坏死因子-cr (TNF) 调节巨噬细胞清道夫受体 (MSR) 的转录和转录后下调 (Hsu, H. Y., Nicholson, A. C., and Hajjar, D. P. (1996) J. Biol. Chem. 271, 7767-7773)；然而，TNF 介导的信号传导机制尚不清楚。在此，我们证明 TNF 受体的连接会刺激 pal 激活蛋白激酶（PAK 和丝裂原激活蛋白激酶 (MAPK)）的活性，如下所示：小鼠巨噬细胞 J774A.1 细胞中的 ERK、JNK 和 p38。激活蛋白激酶 (PK) 后，TNF 会迅速增加 MSR 信息和蛋白质；随后显着降低 MSR 表达。使用 PK 抑制剂和显性失活结构的研究表明磷脂酰肌醇3-激酶/Rac1/PAK/JNK和磷脂酰肌醇3-激酶/Rac1/PAK/p38途径在TNF下调MSR表达和摄取OxLDL中发挥重要作用，或者，通过使用抗TNF-R1激动剂抗体，早期的PKC/MEK1/ERK途径在MSR基因上调中发挥重要作用。此外，在 MSR 基因启动子驱动的荧光素酶报告基因检测中，TNF、PKC 激活剂增加，但抗氧化剂 N-乙酰半胱氨酸、PK 抑制剂和显性失活结构降低了 MSR 基因启动子转染细胞中的荧光素酶活性，而我们目前的结果首次证明了 TMF 介导的 MAPK 通路在 MSR 基因转录调节中的关键作用，并增加了 MSR 表达。 TNF 较长时间的治疗可能通过转录后过程下调 MSR 和泡沫细胞形成。
We previously reported tumor necrosis factor-cr (TNF) modulates transcriptional and post-transcriptional down-regulation of macrophage scavenger receptor (MSR) (Hsu, H. Y., Nicholson, A. C., and Hajjar, D. P. (1996) J. Biol. Chem. 271, 7767-7773); however, TNF-mediated signaling mechanisms are unknown. Here, we demonstrate that ligation of TNF receptor stimulates activity of pal-activated protein kinase (PAK and mitogen-activated protein kinases (MAPK) as follows: ERK, JNK, and p38 in murine macrophage J774A.1 cells. Upon activation of protein kinases (PK), TNF rapidly increases MSR message and protein; later it markedly reduces MSR expression. Studies using PK inhibitors and dominant negative constructs demonstrate phosphatidylinositol 3-kinase/Rac1/PAK/JNK and phosphatidylinositol 3-kinase/Rac1/PAK/p38 pathways contribute to important roles in the late stage of TNF down-regulation of MSR expression and taking up of OxLDL. Alternatively, the PKC/MEK1/ERK pathway in the early stage plays a significant role in up-regulation of the MSR gene. By using anti-TNF-R1 agonist antibody, we further confirm TNF-R1-mediated MAPK in regulation of MSR. Furthermore, in MSR gene promoter-driven luciferase reporter assays with TNF, PKC activator increases, but antioxidant N-acetylcysteine, PK inhibitors, and dominant negative constructs decrease luciferase activity in MSR gene promoter-transfected cells. Our current results show the first evidence of crucial roles for TMF-mediated MAPK pathways in the transcriptional regulation of MSR gene and increase MSR expression; in contrast, with TNF longer treatment the pathways down-regulate MSR and foam cell formation probably via post-transcriptional process.