Mechanisms involved in enhancement of matrix metalloproteinase-9 expression in macrophages by interleukin-33
Mechanisms involved in enhancement of matrix metalloproteinase-9 expression in macrophages by interleukin-33
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DOI：
10.1002/jcp.25809
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发表时间：
2017-12-01
影响因子：
5.6
通讯作者：
Nisihara, Tatsuji
中科院分区：
文献类型：
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作者：
Ariyoshi, Wataru;Okinaga, Toshinori;Nisihara, Tatsuji
巨噬细胞的内皮迁移是通过基质金属蛋白酶(MMPs)诱导的基底膜和细胞外基质成分的降解来完成的。巨噬细胞在免疫挑战时上调基质金属蛋白酶-9的表达和分泌，并在炎症反应中需要其迁移活性。白介素33(IL-33)是新近发现的一种促炎细胞因子，属于IL-1家族。本研究旨在阐明IL-33诱导小鼠单核/巨噬细胞系RAW264.7表达基质金属蛋白酶-9的机制。IL-33促进RAW264.7细胞基质金属蛋白酶-9基因和蛋白的表达。阻断IL-33-IL-33受体(ST2L)结合抑制IL-33介导的基质金属蛋白酶-9的诱导。IL-33诱导细胞外信号调节蛋白1/2(ERK1/2)和核因子-kappaB(NF-B)的磷酸化和核转位。染色质免疫沉淀显示IL-33增加了c-fos对基质金属蛋白酶-9启动子的募集。报告实验结果还显示，IL-33刺激激活蛋白1(AP-1)的转录活性。用ERK1/2和核因子-B的特异性抑制剂处理细胞，可减弱IL-33诱导的AP-1亚单位的激活、AP-1的转录活性和基质金属蛋白酶-9的表达。我们还证明，依赖ERK的cAMP反应元件结合蛋白(CREB)的激活是IL-33激活AP-1的关键步骤。这些结果表明ERK/CREB和NF-B级联信号通路在单核/巨噬细胞通过AP-1活化诱导基质金属蛋白酶-9的过程中起重要作用。
Endothelial transmigration of macrophages is accomplished by matrix metalloproteinase (MMP)-induced degradation of the basement membrane and extracellular matrix components. Macrophages upregulate MMP-9 expression and secretion upon immunological challenges and require its activity for migration during inflammatory responses. Interleukin (IL)-33 is a recently discovered pro-inflammatory cytokine that belongs to the IL-1 family. The aim of this study was to elucidate the mechanisms underlying IL-33-induced MMP-9 expression in the mouse monocyte/macrophage line RAW264.7. IL-33 increased MMP-9 mRNA and protein expression in RAW264.7 cells. Blockage of IL-33-IL-33 receptor (ST2L) binding suppressed IL-33-mediated induction of MMP-9. IL-33 induced phosphorylation and nuclear translocation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-kappa B (NF-B). Chromatin immunoprecipitation indicated that IL-33 increased c-fos recruitment to the MMP-9 promoter. Reporter assay findings also revealed that IL-33 stimulated the transcriptional activity of activator protein 1 (AP-1). Pre-treatment of the cells with a specific inhibitor of ERK1/2 and NF-B attenuated the IL-33-induced activation of AP-1 subunits, transcriptional activity of AP-1, and expression of MMP-9. We also demonstrated that ERK-dependent activation of cAMP response element binding protein (CREB) is a key step for AP-1 activation by IL-33. These results indicate an essential role of ERK/CREB and NF-B cascades in the induction of MMP-9 in monocytes/macrophages through AP-1 activation.