Reddy V Y, Zhang Q Y, Weiss S J
Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3849-53. doi: 10.1073/pnas.92.9.3849.
Human macrophages are believed to damage host tissues in chronic inflammatory disease states, but these cells have been reported to express only modest degradative activity in vitro. However, while examining the ability of human monocytes to degrade the extracellular matrix component elastin, we identified culture conditions under which the cells matured into a macrophage population that displayed a degradative phenotype hundreds of times more destructive than that previously ascribed to any other cell population. The monocyte-derived macrophages synthesized elastinolytic matrix metalloproteinases (i.e., gelatinase B and matrilysin) as well as cysteine proteinases (i.e., cathepsins B, L, and S), but only the cathepsins were detected in the extracellular milieu as fully processed, mature enzymes by either vital fluorescence or active-site labeling. Consistent with these observations, macrophage-mediated elastinolytic activity was not affected by matrix metalloproteinase inhibitors but could be almost completely abrogated by inhibiting cathepsins L and S. These data demonstrate that human macrophages mobilize cysteine proteinases to arm themselves with a powerful effector mechanism that can participate in the pathophysiologic remodeling of the extracellular matrix.
人们认为，人类巨噬细胞在慢性炎症疾病状态下会损害宿主组织，但据报道，这些细胞在体外仅表现出适度的降解活性。然而，在研究人类单核细胞降解细胞外基质成分弹性蛋白的能力时，我们确定了一些培养条件，在此条件下，细胞成熟为巨噬细胞群体，其表现出的降解表型比之前归因于任何其他细胞群体的降解表型具有数百倍的破坏力。单核细胞衍生的巨噬细胞合成了弹性蛋白分解基质金属蛋白酶（即明胶酶B和基质溶素）以及半胱氨酸蛋白酶（即组织蛋白酶B、L和S），但通过活体荧光或活性位点标记，在细胞外环境中仅检测到完全加工成熟的组织蛋白酶。与这些观察结果一致，巨噬细胞介导的弹性蛋白分解活性不受基质金属蛋白酶抑制剂的影响，但通过抑制组织蛋白酶L和S，其活性几乎可以完全消除。这些数据表明，人类巨噬细胞调动半胱氨酸蛋白酶，以一种强大的效应机制武装自己，这种机制可以参与细胞外基质的病理生理重塑。
