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 人单核吞噬细胞加工的金属蛋白酶 肺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， 胶原酶和92 kDa明胶酶，其生产受IFN-γ控制。 γ、IL-4、LPS和I型胶原蛋白。 这些试剂不能改变成纤维细胞来源的细胞因子的释放。 金属蛋白酶我们将研究其生物学功能和表达 新描述的金属蛋白酶，基质溶解素，通过人单核细胞 吞噬细胞这种酶能够降解不溶性弹性蛋白， 蛋白聚糖，并且仅受到TIMP的不良抑制。我们发现， 单核吞噬细胞大量产生基质溶解素 代表了与这种酶相关的第一种人类细胞类型 表情我们将检验基质溶解素对于 基底膜的穿透和间质的穿越 隔栏.我们还将研究TIMP-2的生产，人肺泡 巨噬细胞，其生物合成，我们已经发现，是在一个完全调节 与TIMP-1和间质胶原酶的方式相反（即， 巨噬细胞激活剂（例如LPS）显着诱导间质胶原酶 和TIMP-1，但下调TIMP-2）。这种现象的分子基础 将实行不同的监管。我们的研究将结合细胞 生物学、生物化学和分子生物学方法，包括 侵袭试验，金属蛋白酶的纯化，顺式的阐明 和反式调节元件，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.