Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2.
Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2.
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DOI：
10.4049/jimmunol.0901925
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发表时间：
2009-12-15
期刊：
影响因子：
--
通讯作者：
Falcone DJ
中科院分区：
文献类型：
--
作者：
Steenport M;Khan KM;Du B;Barnhard SE;Dannenberg AJ;Falcone DJ
MMP-9（明胶酶B）参与多种多样的生理和病理过程。最近，我们的特点是环氧化酶-2（考克斯-2）→ PGE 2 → EP 4受体轴，调节巨噬细胞MMP-9的表达。在目前的研究中，我们确定是否MMPs，通常发现在发炎和肿瘤组织，调节前列腺素-EP受体轴，导致MMP-9的表达增强。结果表明，小鼠腹腔巨噬细胞和RAW264.7巨噬细胞暴露于MMP-1（胶原酶-1）或MMP-3（基质溶解素-1）导致考克斯-2表达、PGE 2分泌和随后诱导MMP-9表达的显著增加。在用选择性考克斯-2抑制剂塞来昔布预孵育或用考克斯-2 siRNA转染的巨噬细胞中，蛋白酶诱导的MMP-9表达被阻断。同样，在用EP 4拮抗剂ONO-AE 3 -208预孵育或用EP 4 siRNA转染的巨噬细胞中，蛋白酶诱导的MMP-9被阻断。巨噬细胞暴露于MMP-1和MMP-3可触发TNF-α的快速释放，MMP抑制剂可阻断TNF-α的释放。此外，用抗TNF-α IgG预孵育或用TNF-α siRNA转染的巨噬细胞中，考克斯-2和MMP-9的表达均受到抑制。因此，蛋白酶诱导的巨噬细胞MMP-9表达依赖于TNF-α的释放、考克斯-2表达的诱导和EP 4的PGE 2接合。MMP-1和MMP-3调节巨噬细胞分泌PGE 2和MMP-9表达的能力定义了MMP和前列腺素类之间的联系，其可能在慢性炎性疾病和癌症的发病机制中起作用。这些数据还表明，使用抗TNF-α治疗和/或选择性EP 4拮抗剂可靶向该关系。
MMP-9 (gelatinase B) participates in a variety of diverse physiologic and pathologic processes. We recently characterized a cyclooxygenase-2 (Cox-2)→PGE2→EP4 receptor axis that regulates macrophage MMP-9 expression. In the current studies, we determined whether MMPs, commonly found in inflamed and neoplastic tissues, regulate this prostanoid-EP receptor axis leading to enhanced MMP-9 expression. Results demonstrate that exposure of murine peritoneal macrophages and RAW264.7 macrophages to MMP-1 (collagenase-1) or MMP-3 (stromelysin-1) lead to a marked increase in Cox-2 expression, PGE2 secretion and subsequent induction of MMP-9 expression. Proteinase-induced MMP-9 expression was blocked in macrophages pre-incubated with the selective the Cox-2 inhibitor celecoxib or transfected with Cox-2 siRNA. Likewise, proteinase-induced MMP-9 was blocked in macrophages pre-incubated with the EP4 antagonist ONO-AE3-208 or transfected with EP4 siRNA. Exposure of macrophages to MMP-1 and MMP-3 triggered the rapid release of TNF-α, which was blocked by MMP-inhibitors. Furthermore, both Cox-2 and MMP-9 expression were inhibited in macrophages pre-incubated with anti-TNF-α IgG or transfected with TNF-α siRNA. Thus, proteinase-induced MMP-9 expression by macrophages is dependent on the release of TNF-α, induction of Cox-2 expression and PGE2 engagement of EP4. The ability of MMP-1 and -3 to regulate macrophage secretion of PGE2 and expression of MMP-9 defines a nexus between MMPs and prostanoids that is likely to play a role in the pathogenesis of chronic inflammatory diseases and cancer. These data also suggest that this nexus is targetable utilizing anti-TNF-α therapies and/or selective EP4 antagonists.
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影响因子：
4.8
作者：
Khan, KMF;Laurie, GW;Falcone, DJ
通讯作者：
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影响因子：
10.6
作者：
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通讯作者：
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DOI：
10.1161/01.atv.0000177814.41505.41
发表时间：
2005-09-01
影响因子：
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作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
4.8
作者：
Hendrickx, N;Volanti, C;Agostinis, P
通讯作者：
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