Weber Georg F, Zawaideh Samer, Hikita Sherry, Kumar Vikram A, Cantor Harvey, Ashkar Samy
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Binney Street, Boston, Massachusetts, USA.
J Leukoc Biol. 2002 Oct;72(4):752-61.
Neutrophil-independent macrophage responses are a prominent part of delayed-type immune and healing processes and depend on T cell-secreted cytokines. An important mediator in this setting is the phosphoprotein osteopontin, whose secretion by activated T cells confers resistance to infection by several intracellular pathogens through recruitment and activation of macrophages. Here, we analyze the structural basis of this activity following cleavage of the phosphoprotein by thrombin into two fragments. An interaction between the C-terminal domain of osteopontin and the receptor CD44 induces macrophage chemotaxis, and engagement of beta(3)-integrin receptors by a nonoverlapping N-terminal osteopontin domain induces cell spreading and subsequent activation. Serine phosphorylation of the osteopontin molecule on specific sites is required for functional interaction with integrin but not CD44 receptors. Thus, in addition to regulation of intracellular enzymes and substrates, phosphorylation also regulates the biological activity of secreted cytokines. These data, taken as a whole, indicate that the activities of distinct osteopontin domains are required to coordinate macrophage migration and activation and may bear on incompletely understood mechanisms of delayed-type hypersensitivity, wound healing, and granulomatous disease.
不依赖中性粒细胞的巨噬细胞反应是迟发型免疫和愈合过程的一个重要组成部分，且依赖于T细胞分泌的细胞因子。在这种情况下，一种重要的介质是磷蛋白骨桥蛋白，活化的T细胞分泌的骨桥蛋白通过招募和激活巨噬细胞赋予对几种细胞内病原体感染的抵抗力。在此，我们分析了凝血酶将该磷蛋白切割成两个片段后这种活性的结构基础。骨桥蛋白的C末端结构域与受体CD44之间的相互作用诱导巨噬细胞趋化，而不重叠的N末端骨桥蛋白结构域与β(3)-整合素受体的结合诱导细胞铺展及随后的激活。骨桥蛋白分子在特定位点的丝氨酸磷酸化是与整合素而非CD44受体进行功能相互作用所必需的。因此，除了调节细胞内酶和底物外，磷酸化还调节分泌的细胞因子的生物学活性。总体而言，这些数据表明，不同的骨桥蛋白结构域的活性是协调巨噬细胞迁移和激活所必需的，可能与迟发型超敏反应、伤口愈合和肉芽肿病等尚未完全了解的机制有关。
