Transforming growth factor-β- and tumor necrosis factor-α-mediated induction and proteolytic activation of MMP-9 in human skin
Transforming growth factor-β- and tumor necrosis factor-α-mediated induction and proteolytic activation of MMP-9 in human skin
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DOI：
10.1074/jbc.m010839200
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发表时间：
2001-06-22
影响因子：
4.8
通讯作者：
Garner, WL
中科院分区：
文献类型：
--
作者：
Han, YP;Tuan, TL;Garner, WL
细胞因子和基质金属蛋白酶（MMPs）在肿瘤转移和伤口修复等生理和病理过程中都具有活性。我们系统地研究了细胞因子介导的MMP调控。细胞因子介导的蛋白酶诱导和激活最初在器官培养的人皮肤中进行了研究，随后使用分离的皮肤细胞确定了潜在的细胞和分子机制。在本报告中，我们证明肿瘤坏死因子- α (tnf - α)和转化生长因子- β (tgf - β)协同诱导人皮肤以及分离的真皮成纤维细胞和表皮角质形成细胞中的前mmp -9。此外，tnf - α通过将92kda的pro-MMP-9转化为82kda的活性酶，促进pro-MMP-9的蛋白水解活化。这种激活仅发生在皮肤器官培养中，而不是在分离的成纤维细胞或角质形成细胞中，尽管可以在tnf - α激活皮肤的无细胞系统中测量到前mmp -9的激活。在转录水平上，我们检测了细胞因子介导的人MMP-9的5'区启动子在真皮成纤维细胞中的反激活。结果表明，tnf - α和tgf - β可以独立刺激5'侧670碱基对启动子。一个tgf - β反应元件（-474）和一个nf - kappab结合位点（-601）分别被鉴定为TGF-P或tnf - α激活的顺式元件。综上所述，这些发现表明多种细胞因子可以调节人体皮肤细胞中MMP-9的表达/激活的特定机制。这些结果暗示了这些细胞因子在调节MMP-9在生理性和病理性组织重塑中的作用。
Both cytokines and matrix metalloproteinases (MMPs) are active during physiologic and pathologic processes such as cancer metastasis and wound repair. We have systematically studied cytokine-mediated MMP regulation. Cytokine-mediated proteinase induction and activation were initially investigated in organ-cultured human skin followed by determination of underlying cellular and molecular mechanisms using isolated skin cells. In this report we demonstrate that tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) synergistically induce pro-MMP-9 in human skin as well as isolated dermal fibroblasts and epidermal keratinocytes. Furthermore, TNF-alpha promotes proteolytic activation of pro-MMP-9 by conversion of the 92-kDa pro-MMP-9 to the 82-kDa active enzyme. This activation occurred only in skin organ culture and not by either isolated fibroblasts or keratinocyte, although the pro-MMP-9 activation could be measured in a cell-free system derived from TNF-alpha -activated skin. The cytokine-mediated induction of pro-MMP-9 in dermal fibroblasts was evident by increased mRNA At the transcription level, we examined the cytokine-mediated transactivation of the 5'-region promoter of the human MMP 9 in dermal fibroblasts. The results demonstrated that TNF-alpha and TGF-beta could independently stimulate the 5'-flanking 670-base pair promoter. A TGF-beta -response element (-474) and an NF-kappaB-binding site (-601) were identified to be the cis-elements for TGF-P or TNF-alpha activation, respectively. Taken together, these findings suggest a specific mechanism whereby multiple cytokines can regulate MMP-9 expression/activation in the cells of human skin. These results imply roles for these cytokines in the regulation of MMP-9 in physiologic and pathologic tissue remodeling.