Regulation of Hepatic Fibrosis and Extracellular Matrix Genes by the Th Response: New Insight into the Role of Tissue Inhibitors of Matrix Metalloproteinases
Regulation of Hepatic Fibrosis and Extracellular Matrix Genes by the Th Response: New Insight into the Role of Tissue Inhibitors of Matrix Metalloproteinases
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DOI：
10.4049/jimmunol.167.12.7017
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发表时间：
2001-12
期刊：
影响因子：
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通讯作者：
B. Vaillant;M. Chiaramonte;A. Cheever;P. Soloway;T. Wynn
中科院分区：
文献类型：
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作者：
B. Vaillant;M. Chiaramonte;A. Cheever;P. Soloway;T. Wynn
肝纤维化是曼氏血吸虫感染的标志，经常导致门脉高压和食道静脉曲张出血。纤维化过程高度依赖于2型细胞因子，但它们在调节细胞外基质重塑基因中的作用仍很不清楚。在这里，我们检测了基质金属蛋白酶(MMPs)-2、-3、-9、-12和-13及其抑制物金属蛋白酶组织抑制物(TIMP)-1、-2和-3在感染小鼠肝脏中的表达，并将它们的表达谱与纤维化和2型细胞因子的产生联系起来。感染小鼠在产卵开始时，MMP-2、-3、-9、-12、-13和TIMP-1、-2mRNA的表达迅速增加，而TIMP-3的表达没有变化。由于TIMP被认为是细胞外基质的重要调节因子，并且它们的表达与纤维化的发展相关，因此我们通过感染TIMP-1和TIMP-2缺陷小鼠来研究它们在纤维化形成中的作用。值得注意的是，我们的数据显示TIMP-1或TIMP-2在曼氏血吸虫虫卵诱导的纤维化病理中没有作用。由于这些发现，我们感染了IL-10/干扰素-γ缺陷小鼠，这些小鼠产生了夸大的纤维化反应，以确定2型细胞因子优势地位的变化是否影响基质金属蛋白酶和基质金属蛋白酶的表达模式。纤维化和2型细胞因子的产生与MMP2/MMP9和TIMP-1/TIMP-2的表达增加相关。这些数据，加上我们的基因敲除研究，表明TIMP-1/TIMP-2在血吸虫病的纤维化形成中没有重要作用。事实上，我们的研究结果表明，抑制促纤维化细胞因子或特定的基质金属蛋白酶可能是改善纤维化病理的更有效的策略。
Hepatic fibrosis is the hallmark of Schistosoma mansoni infection and often results in portal hypertension and bleeding from esophageal varices. The fibrotic process is highly dependent on type 2 cytokines, yet their role in the regulation of extracellular matrix remodeling genes remains largely unknown. Here, we examined the expression of matrix metalloproteases (MMP) -2, -3, -9, -12, and -13 and their inhibitors, tissue inhibitor of metalloproteases (TIMP) -1, -2, and -3, in the livers of infected mice and correlated their expression profiles with fibrosis and type 2 cytokine production. Expression of MMP-2, -3, -9, -12, and -13 and of TIMP-1 and -2 mRNA rapidly increased at the onset of egg laying in infected mice, while TIMP-3 was unchanged. Because TIMP are presumed to be important regulators of the extracellular matrix, and their expression correlated with the development of fibrosis, we studied their role in fibrogenesis by infecting TIMP-1- and TIMP-2-deficient mice. Strikingly, our data revealed no role for TIMP-1 or -2 in the fibrotic pathology induced by S. mansoni eggs. Because of these findings, we infected IL-10/IFN-γ-deficient mice that develop an exaggerated fibrotic response to determine whether changes in type 2 cytokine dominance influence the pattern of MMP and TIMP expression. Fibrosis and type 2 cytokine production correlated with increased MMP-2/MMP-9 vs TIMP-1/TIMP-2 expression. These data, in addition to our knockout studies, demonstrate that TIMP-1/TIMP-2 play no essential role in fibrogenesis in schistosomiasis. Indeed, our findings suggest that inhibiting profibrotic cytokines or specific MMP may be a more effective strategy to ameliorate fibrotic pathology.