Human leukocyte elastase is an endogenous ligand for the integrin CR3 (CD11b/CD18, Mac-1, alpha(M)beta(2)) and modulates polymorphonuclear leukocyte adhesion
Human leukocyte elastase is an endogenous ligand for the integrin CR3 (CD11b/CD18, Mac-1, alpha(M)beta(2)) and modulates polymorphonuclear leukocyte adhesion
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DOI：
10.1084/jem.184.4.1213
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发表时间：
1996-10-01
影响因子：
15.3
通讯作者：
Wright, SD
中科院分区：
文献类型：
--
作者：
Cai, TQ;Wright, SD
整合素CR 3（CD 11b/CD 18，Mac-1，alpha（M）beta（2））介导多形核白细胞（PMN）与纤维蛋白原、C3 bi、ICAM-1和其他配体包被的表面的瞬时粘附。最近的研究（蔡，T.-问：和S.D.赖特1995. J.Biol.Chem.270：14358）表明，粘附可能受到CR 3的配体结合动力学的刺激依赖性变化的促进。另一方面，细胞脱离必须通过不同的机制发生，因为结合动力学在配体结合发生后不能影响细胞粘附。我们已经寻找了一种机制，将逆转配体结合CR 3和报告在这里，PMN的裂解物含有内源性配体，结合CR 3和竞争的结合C3 bi。纯化和序列分析确定了结构同源的嗜天青颗粒蛋白，弹性蛋白酶，蛋白酶3，和azurocidin作为候选人。与纯化的弹性蛋白酶和azurocidin的研究表明，各自特异性地结合到纯化的，固定的CR 3。弹性蛋白酶可能在调节整合素介导的细胞粘附中起作用，因为它在细胞表面表达，并且表达水平与细胞粘附性成反比。此外，抗弹性蛋白酶的单克隆抗体可防止PMN从纤维蛋白原包被的表面上脱落，并阻断趋化性，证实了这种蛋白质在调节整合素介导的粘附中的作用。这些研究提出了一种释放整合素介导的细胞粘附的模型，其中内源性配体如弹性蛋白酶可以通过“洗脱”底物结合的配体来释放粘附。弹性蛋白酶的蛋白水解活性的作用似乎是可能的，但在这项研究中没有得到证实。
Integrin CR3 (CD11b/CD18, Mac-1, alpha(M) beta(2)) mediates the transient adhesion of polymorphonuclear leukocytes (PMN) to surfaces coated with fibrinogen, C3bi, ICAM-1, and other ligands. Recent studies (Cai, T.-Q., and S.D. Wright. 1995. J. Biol. Chem. 270:14358) suggest that adhesion may be favored by stimulus-dependent changes in the kinetics of ligand binding by CR3. Cell detachment, on the other hand, must occur by a different mechanism because binding kinetics cannot affect cell adhesion after binding of ligand has occurred. We have sought a mechanism that would reverse binding of ligand to CR3 and report here that lysates of PMN contain an endogenous ligand that binds CR3 and competes the binding of C3bi. Purification and sequence analysis identified the structurally homologous azurophilic granule proteins, elastase, protease 3, and azurocidin as candidates. Studies with purified elastase and azurocidin showed that each bound specifically to purified, immobilized CR3. Elastase may play a role in modulating integrin-mediated cell adhesion because it is expressed at the cell surface, and the expression level is inversely proportional to cell adhesivity. Furthermore, a monoclonal antibody against elastase prevented detachment of PMN from fibrinogen-coated surfaces and blocked chemotaxis, confirming a role for this protein in regulating integrin-mediated adhesion. These studies suggest a model for release of integrin-mediated cell adhesion in which endogenous ligands such as elastase may release adhesion by ''eluting'' substrate-bound ligand. A role for the proteolytic activity of elastase appears likely but is not demonstrated in this study.