Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen
Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen
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DOI：
10.1074/jbc.m310999200
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发表时间：
2004-02-06
影响因子：
4.8
通讯作者：
Tsukamoto, H
中科院分区：
文献类型：
--
作者：
Han, YP;Zhou, L;Tsukamoto, H
肝星状细胞(HSC)位于肝窦周隙，被细胞外基质包围，在肝纤维化形成过程中经历表型转分化，称为肌成纤维细胞激活。本研究探讨白细胞介素1(IL-1α)对生长在三维细胞外基质中的HSC表达基质金属蛋白酶(MMPs)的调节作用及其在HSC活化中的作用。为了重述体内HSC的“静止”状态，将分离的大鼠HSC培养在三维Matrigel或I型胶原中。当HSC在这些基质中培养时，IL-1α刺激可强烈诱导基质金属蛋白酶-9的前体-基质金属蛋白酶-9的表达。只有当细胞处于I型胶原时，IL-1α才能诱导原-基质金属蛋白酶-9向活性形式转化。在胶原蛋白晶格中，IL-1α通过诱导基质金属蛋白酶-13、基质金属蛋白酶-3和基质的分解来刺激肝星状细胞的激活。用金属蛋白酶组织抑制物-1处理细胞或去除基质金属蛋白酶-9可完全阻止HSC的激活。一旦完全激活，HSC不表达基质金属蛋白酶-9，对基质金属蛋白酶-13和基质金属蛋白酶-3的诱导减弱。此外，我们还发现α-平滑肌肌动蛋白和基质金属蛋白酶-9在人肝纤维化组织中的肝星状细胞亚群中共定位。因此，本研究提供了一个新的模型来阐明MMPs，尤其是基质金属蛋白酶-9在肝纤维化过程中受特定细胞因子调节的HSC激活中的作用。
Located within the perisinusoidal space and surrounded by extracellular matrix, hepatic stellate cells (HSC) undergo phenotypic trans-differentiation called "myofibroblastic activation" in liver fibrogenesis. This study investigated the regulation of interleukin-1 (IL-1alpha) on expression of matrix metalloproteinases (MMPs) by HSC grown in three-dimensional extracellular matrix and the role of MMPs in HSC activation. To recapitulate the in vivo "quiescent" state of HSC, the isolated rat HSC were grown in three-dimensional Matrigel or type I collagen. Stimulation with IL-1alpha caused robust induction of pro-MMP-9 (the precursor of matrix metalloproteinase-9) when HSC were cultured in these matrices. IL-1alpha induced a conversion of the pro-MMP-9 to the active form only when the cells were in type I collagen. In collagen lattices, IL-1alpha provoked activation of HSC with induction of MMP-13, MMP-3, and breakdown of the matrix. The HSC activation was completely prevented by a treatment of the cells with tissue inhibitor of metalloproteinase-1 or deprivation of MMP-9. Once fully activated, HSC failed to express MMP-9 and showed attenuated induction of MMP-13 and MMP-3. Further, we demonstrated colocalization of alpha-smooth muscle actin and MMP-9 in a subpopulation of HSC in human fibrotic liver tissues. Thus, this study provides a novel model to enlighten the role of MMPs, particularly that of MMP-9, in HSC activation regulated by a specific cytokine in liver fibrogenesis.