Mariani T J, Sandefur S, Roby J D, Pierce R A
Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.
Mol Biol Cell. 1998 Jun;9(6):1411-24. doi: 10.1091/mbc.9.6.1411.
The mechanisms responsible for the induction of matrix-degrading proteases during lung injury are ill defined. Macrophage-derived mediators are believed to play a role in regulating synthesis and turnover of extracellular matrix at sites of inflammation. We find a localized increase in the expression of the rat interstitial collagenase (MMP-13; collagenase-3) gene from fibroblastic cells directly adjacent to macrophages within silicotic rat lung granulomas. Conditioned medium from macrophages isolated from silicotic rat lungs was found to induce rat lung fibroblast interstitial collagenase gene expression. Conditioned medium from primary rat lung macrophages or J774 monocytic cells activated by particulates in vitro also induced interstitial collagenase gene expression. Tumor necrosis factor-alpha (TNF-alpha) alone did not induce interstitial collagenase expression in rat lung fibroblasts but did in rat skin fibroblasts, revealing tissue specificity in the regulation of this gene. The activity of the conditioned medium was found to be dependent on the combined effects of TNF-alpha and 12-lipoxygenase-derived arachidonic acid metabolites. The fibroblast response to this conditioned medium was dependent on de novo protein synthesis and involved the induction of nuclear activator protein-1 activity. These data reveal a novel requirement for macrophage-derived 12-lipoxygenase metabolites in lung fibroblast MMP induction and provide a mechanism for the induction of resident cell MMP gene expression during inflammatory lung processes.
肺损伤期间诱导基质降解蛋白酶的机制尚不明确。巨噬细胞衍生的介质被认为在炎症部位调节细胞外基质的合成和周转中发挥作用。我们发现，在硅沉着病大鼠肺肉芽肿中，紧邻巨噬细胞的成纤维细胞中大鼠间质胶原酶（MMP-13；胶原酶-3）基因的表达出现局部增加。研究发现，从硅沉着病大鼠肺中分离出的巨噬细胞的条件培养基可诱导大鼠肺成纤维细胞间质胶原酶基因表达。体外被颗粒物激活的原代大鼠肺巨噬细胞或J774单核细胞的条件培养基也能诱导间质胶原酶基因表达。单独的肿瘤坏死因子-α（TNF-α）不会诱导大鼠肺成纤维细胞中的间质胶原酶表达，但会诱导大鼠皮肤成纤维细胞中的表达，这揭示了该基因调控中的组织特异性。研究发现，条件培养基的活性依赖于TNF-α和12-脂氧合酶衍生的花生四烯酸代谢产物的联合作用。成纤维细胞对这种条件培养基的反应依赖于从头合成蛋白质，并涉及核激活蛋白-1活性的诱导。这些数据揭示了巨噬细胞衍生的12-脂氧合酶代谢产物在肺成纤维细胞MMP诱导中的新需求，并为炎症性肺过程中驻留细胞MMP基因表达的诱导提供了一种机制。
