Cell-surface heparan sulfate proteoglycan-mediated regulation of human neutrophil migration by the serpin antithrombin III
Cell-surface heparan sulfate proteoglycan-mediated regulation of human neutrophil migration by the serpin antithrombin III
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DOI：
10.1182/blood.v97.4.1079
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发表时间：
2001-02-15
期刊：
影响因子：
20.3
通讯作者：
Wiedermann, CJ
中科院分区：
文献类型：
--
作者：
Dunzendorfer, S;Kaneider, N;Wiedermann, CJ
据报道，丝氨酸蛋白酶抑制剂抗凝血酶 III (AT III) 具有止血调节和抗炎特性。为了确定其影响不依赖凝血酶的白细胞反应的能力，研究了 AT III 浓缩物 Kybernin P 和单克隆抗体纯化的 AT III 对中性粒细胞迁移的直接影响。在改良的博伊登微趋化室中测定从健康供体的血液中分离出的人类中性粒细胞的趋化活性，并根据标准实验方案进行结合研究。中性粒细胞与 Kybernin P 或免疫吸附 AT iii 体外预孵育，以浓度依赖性方式显着抑制向 fMet-Leu-Phe 或白细胞介素 8 (IL-8) 的迁移。在没有额外引诱剂的情况下，中性粒细胞表现出对 AT III 制剂梯度的迁移反应。棋盘实验证实了真正的趋化性。分析表明，AT III肝素结合位点与中性粒细胞膜相关的硫酸乙酰肝素蛋白聚糖受体相互作用，细胞内信号传导机制不同； IL-8 诱导的趋化性失活是由于 AT III 信号与 IL-8 信号转导途径的酪氨酸磷酸酶敏感性相互作用所致，而 AT III 诱导的趋化性涉及蛋白激酶 C 和磷酸二酯酶。 AT III 和蛋白聚糖 syndecan-4 之间的信号相似性可能表明 AT III 与这种新型膜受体的结合。在生理条件下，AT III 可以防止中性粒细胞过早激活。此外，全身施用 AT III 浓缩物可能对对抗全身炎症产生有益作用。 (c) 2001 年，美国血液学会
The serpin antithrombin III (AT III) is reported to have hemostasis-regulating and anti-inflammatory properties. To determine its ability to influence thrombin-independent leukocyte responses, the direct effects of the AT III concentrate Kybernin P and a monoclonal antibody-purified AT III on neutrophil migration were studied. Chemotactic activity of human neutrophils isolated from the blood of healthy donors was determined in modified Boyden microchemotaxis chambers, and binding studies were performed according to standard experimental protocols. Preincubation in vitro of neutrophils with Kybernin P or immune-adsorbed AT iii significantly deactivated migration toward fMet-Leu-Phe, or interleukin-8 (IL-8), in a concentration-dependent manner. In the absence of additional attractants, neutrophils exhibited a migratory response toward gradients of AT III preparations. True chemotaxis was confirmed in checkerboard assays. Analyses revealed that the AT III heparin-binding site interacts with neutrophil membrane-associated heparan sulfate proteoglycan receptors, Mechanisms of intracellular signaling differed; the deactivation of IL-8-induced chemotaxis resulted from tyrphostin-sensitive interactions of AT III-signaling with the IL-8 signal transduction pathway, whereas AT III-induced chemotaxis involved protein kinase C and phosphodiesterases. Signaling similarities between AT III and the proteoglycan syndecan-4 may suggest the binding of AT III to this novel type of membrane receptor. Under physiological conditions, AT III may prevent neutrophils from premature activation. Moreover, the systemic administration of AT III concentrate could have beneficial effects in combating systemic inflammation. (c) 2001 by The American Society of Hematology