Unexpected transcriptional induction of monocyte chemoattractant protein 1 by proteasome inhibition: Involvement of the c-Jun N-terminal kinase-activator protein 1 pathway
Unexpected transcriptional induction of monocyte chemoattractant protein 1 by proteasome inhibition: Involvement of the c-Jun N-terminal kinase-activator protein 1 pathway
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DOI：
10.4049/jimmunol.167.3.1145
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发表时间：
2001-08-01
影响因子：
4.4
通讯作者：
Kitamura, M
中科院分区：
文献类型：
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作者：
Nakayama, K;Furusu, A;Kitamura, M
蛋白酶体抑制剂，众所周知的NF-κ B抑制剂，最近被认为是炎症的治疗剂。然而，这些药物的抗炎特性尚未得到充分评价。在这份报告中，我们描述了一种新的影响蛋白酶体抑制剂的表达单核细胞趋化蛋白1（MCP-1）在系膜细胞。我们发现，蛋白酶体抑制剂MG 132剂量依赖性地诱导MCP-1在转录水平上的表达。在其他蛋白酶体抑制剂（蛋白酶体抑制剂I和lactacystin）和其他细胞类型（NRK成纤维细胞）中观察到类似的刺激作用。MCP-1基因的5 '侧翼区含有多个AP-1位点。为了探索相关机制，我们研究了蛋白酶体抑制对AP-1通路的影响。北方印迹分析显示，MG 132能快速诱导e-jun的表达，但不能诱导c-fos的表达。免疫印迹分析表明，MG 132阻止c-Jun蛋白的降解。激酶活性测定显示MG 132可迅速激活c-Jun N-末端激酶（JNK）。与这些结果一致，报告基因测定显示，用MG 132处理后AP-1活性上调。姜黄素是JNK-AP-1途径的药理学抑制剂，可消除MG 132对MCP-1的诱导作用。类似地，用c-Jun的显性负突变体稳定转染减弱了MG 132诱导的AP-1活化和MCP-1表达。不仅在MCP-1中观察到蛋白酶体抑制剂的转录激活，而且在其他AP-1依赖性基因中也观察到蛋白酶体抑制剂的转录激活，包括基质分解素和丝裂原活化蛋白激酶磷酸酶1。这些数据表明，蛋白酶体抑制通过JNK-c-jun/AP-1通路的多步诱导触发MCP-1和其他基因的表达。
Proteasome inhibitors, the well-known inhibitors of NF-kappaB are recently considered therapeutic agents for inflammation. However, the anti-inflammatory properties of these agents have not been fully evaluated. In this report we describe a novel effect of proteasome inhibitors on the expression of monocyte chemoattractant protein 1 (MCP-1) in mesangial cells. We found that proteasome inhibitor MG132 dose-dependently induced expression of MCP-1 at the transcriptional level. The stimulatory effect was similarly observed with other proteasome inhibitors (proteasome inhibitor I and lactacystin) and in other cell types (NRK fibroblasts). The 5'-flanking region of the MCP-1 gene contains multiple AP-1 sites. To explore the mechanisms involved, we examined the effects of proteasome inhibition on the AP-1 pathway. Northern blot analysis showed that MG132 rapidly induced the expression of e-jun, but not c-fos. Immunoblot analysis showed that MG132 prevented degradation of c-Jun protein. Kinase assay revealed that c-Jun N-terminal kinase (JNK) was rapidly activated by MG132. Consistent with these results, a reporter assay showed that AP-1 activity was up-regulated after treatment with MG132. Curcumin, a pharmacological inhibitor of the JNK-AP-1 pathway, abrogated the induction of MCP-1 by MG132. Similarly, stable transfection with a dominant-negative mutant of c-Jun attenuated both MG132-induced activation of AP-1 and expression of MCP-1. The transcriptional activation by proteasome inhibitors was observed not only in MCP-1, but also in other AP-1-dependent genes, including stromelysin and mitogen-activated protein kinase phosphatase 1. These data revealed that proteasome inhibition triggered the expression of MCP-1 and other genes via the multistep induction of the JNK-c-jun/AP-1 pathway.