EXPRESSION OF MATRIX METALLOPROTEINASES BY MONOCYTES AND ROLE IN LUNG BIOLOGY

本项目的目标是研究矩阵的作用 人单核巨噬细胞表达的金属蛋白酶 肺部生物学。我们将研究基因调控的分子机制。 肺泡巨噬细胞的两种主要金属蛋白酶：间质 胶原酶和92 kDa明胶酶，其产量受干扰素-β控制。 γ、IL-4、内毒素和I型胶原以细胞类型特异的方式表达。 这些药物不能改变成纤维细胞来源的释放 金属蛋白酶。我们将研究其生物学功能和表达。 人单核细胞表达新发现的金属蛋白酶--基质溶素 吞噬细胞。这种酶能够降解不溶的弹性蛋白和 蛋白多糖，只被TIMPs抑制得很差。我们的发现是 单核吞噬细胞发育过程中大量产生基质溶血素 代表了与这种酶有关的第一种人类细胞类型S 表情。我们将检验这一假设，即母溶素对 基底膜的穿透和间质的穿透 障碍。我们还将研究人肺泡细胞产生TIMP-2的情况 巨噬细胞，我们已经发现其生物合成受到完全 与TIMP-1和间质胶原酶相反的方式(即， 巨噬细胞激活剂如内毒素可显著诱导间质胶原酶 和TIMP-1，但下调TIMP-2)。这种现象的分子基础 将实行完全不同的监管。我们的研究将把细胞 生物学、生物化学和分子生物学方法，包括 侵袭实验、金属蛋白酶的纯化、顺式作用的阐明 和反式调控元件，以及原位杂交。

The objective of this project is to examine the role of matrix metalloproteinases elaborated by human mononuclear phagocytes in human lung biology. We will study molecular mechanisms of the gene regulation of the alveolar macrophage's two principal metalloproteinases, interstitial collagenase and 92 kDa gelatinase, whose production is controlled by IFN- gamma, IL-4, LPS, and type I collagen in a cell type-specific manner. These agents fail to modify the release of fibroblast-derived metalloproteinases. We will study the biological function and expression of the newly-described metalloproteinase, matrilysin, by human mononuclear phagocytes. This enzyme is capable of degrading insoluble elastin and proteoglycans and is only poorly inhibited by TIMPs. Our finding of extensive matrilysin production by developing mononuclear phagocytes represents the first human cell type associated with this enzyme s expression. We will test the hypothesis that matrilysin is important for the penetration of basement membranes and the traversing of interstitial barriers. We will also study the production of TIMP-2 by human alveolar macrophages, whose biosynthesis we have found is regulated in a completely opposite manner to that of TIMP-1 and interstitial collagenase (i.e., macrophage activators such as LPS markedly induce interstitial collagenase and TIMP-1, but downregulate TIMP-2). The molecular basis for such disparate regulation will be pursued. Our studies will incorporate cell biology, biochemistry, and molecular biologic approaches, including invasion assays, purification of metalloproteinases, elucidation of cis and trans regulatory elements, and in situ hybridization.