Bell Jessica H, Herrera Amy H, Li Ying, Walcheck Bruce
Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota 55108, USA.
J Leukoc Biol. 2007 Jul;82(1):173-6. doi: 10.1189/jlb.0307193. Epub 2007 May 17.
TNF-alpha and its receptors TNFRI and TNFRII are cleaved from the surface of leukocytes by a proteolytic process referred to as ectodomain shedding. The role of a disintegrin and metalloproteinase 17 (ADAM17) in this process by the major professional phagocytes neutrophils and macrophages, the primary producers of TNF-alpha during inflammation induction, is based entirely on indirect evidence, and other sheddases have been implicated as well. As Adam17 gene-targeting in mice is lethal, we assessed the protease's relative contribution to TNF-alpha, TNFRI, and TNFRII shedding using radiation chimeric mice with leukocytes lacking functional ADAM17. We report ablated, soluble TNF-alpha, TNFRI, and TNFRII production by neutrophils and macrophages stimulated with various microbial antigens and greatly reduced TNF-alpha levels in vivo following inflammation induction. This is the first simultaneous analysis of TNF-alpha, TNFRI, and TNFRII shedding by neutrophils and macrophages and the first direct evidence that ADAM17 is a primary and nonredundant sheddase.
肿瘤坏死因子-α（TNF-α）及其受体TNFRI和TNFRII通过一种称为胞外域脱落的蛋白水解过程从白细胞表面裂解下来。在炎症诱导期间TNF-α的主要产生者、主要的专业吞噬细胞中性粒细胞和巨噬细胞中，解整合素和金属蛋白酶17（ADAM17）在这一过程中的作用完全基于间接证据，并且其他脱落酶也被牵连其中。由于小鼠中的Adam17基因靶向是致死性的，我们使用缺乏功能性ADAM17的白细胞的辐射嵌合小鼠评估了该蛋白酶对TNF-α、TNFRI和TNFRII脱落的相对贡献。我们报告了用各种微生物抗原刺激的中性粒细胞和巨噬细胞中可溶性TNF-α、TNFRI和TNFRII产生的缺失，以及炎症诱导后体内TNF-α水平的大幅降低。这是首次对中性粒细胞和巨噬细胞的TNF-α、TNFRI和TNFRII脱落进行同时分析，也是ADAM17是主要且非冗余脱落酶的首个直接证据。
