Immobilized stromal cell-derived factor-1α triggers rapid VLA-4 affinity increases to stabilize lymphocyte tethers on VCAM-1 and subsequently initiate firm adhesion
Immobilized stromal cell-derived factor-1α triggers rapid VLA-4 affinity increases to stabilize lymphocyte tethers on VCAM-1 and subsequently initiate firm adhesion
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DOI：
10.4049/jimmunol.178.6.3903
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Lawrence, Michael B.
中科院分区：
文献类型：
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作者：
DiVietro, Jeffrey A.;Brown, David C.;Lawrence, Michael B.
整合素VLA-4(α(4)β(1))介导拴系和滚动事件以及白细胞与VCAM-1的牢固黏附。与选择素不同，VLA-4整合素介导的淋巴细胞黏附可以通过细胞内信号通路受到趋化因子的调节。为了研究趋化因子基质细胞衍生因子-1α(SDF-1α)对VLA-4介导的淋巴细胞黏附的影响，在平行平板流动室中，人PBL在VCAM-1底物上流动，表面固定化SDF-1α是一种有效的黏附激活剂。最初的拴系相互作用的平均寿命为200ms，与低亲和力的VLA-4-VCAM-1键的半衰期一致。固定化的SDF-1α在初级系绳的寿命内起作用，以稳定初始系绳相互作用，增加PBL与表面保持相互作用的可能性。正如预期的那样，固定化的SDF-1α还增加了PBL牢固的粘附率和滚动比。一种基于LDV多肽的小分子优先结合高亲和力的VLA-4，将PBL与VCAM-1的粘附性降低了90%。由于高亲和力VLA-4的阻断而导致的牢固粘附性的减少与滚动PBL比例的4倍增加是平行的。趋化因子激活PBL在VCAM-1上的牢固黏附依赖于高亲和力VLA-4的诱导，而不是像以前认为的那样招募预先存在的高亲和力VLA-4池。
The integrin VLA-4 (alpha(4)beta(1)) mediates tethering and rolling events as well as firm adhesion of leukocytes to VCAM-1. Unlike selectins, VLA-4 integrin-mediated lymphocyte adhesiveness can be modulated by chemokines through intracellular signaling pathways. To investigate the effects of the chemokine stromal cell-derived factor-1 alpha (SDF-1 alpha) on VLA-4-mediated lymphocyte adhesion, human PBL were flowed over VCAM-1 substrates in a parallel plate flow chamber with surface-immobilized SDF-1 alpha, a potent activator of firm adhesion. The initial tethering interactions had a median lifetime of 200 ms, consistent with the half-life of low-affinity VLA-4-VCAM-1 bonds. Immobilized SDF-1 alpha acted within the lifetime of a primary tether to stabilize initial tethering interactions, increasing the likelihood a PBL would remain interacting with the surface. As expected, the immobilized SDF-1 alpha also increased the ratio of PBL firm adhesion to rolling. An LDV peptide-based small molecule that preferentially binds high-affinity VLA-4 reduced PBL firm adhesion to VCAM-1 by 90%. The reduction in firm adhesion due to blockage of high-affinity VLA-4 was paralleled by a 4-fold increase in the fraction of rolling PBL. Chemokine activation of PBL firm adhesion on VCAM-1 depended on induction of high-affinity VLA-4 rather than recruitment of a pre-existing pool of high-affinity VLA-4 as previously thought.