Nielsen M, Svejgaard A, Skov S, Dobson P, Bendtzen K, Geisler C, Odum N
Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.
J Immunol. 1996 Dec 15;157(12):5350-8.
Besides its function as a growth factor, IL-2 induces beta2-integrin-dependent, homotypic adhesion of IL-2R-positive T cells. In this study, we investigated how IL-2R are functionally and biochemically linked to the beta2-integrin adhesion pathway. After a lag period of 15 to 20 min, IL-2 induces beta2-integrin-dependent, homotypic adhesion in Ag-specific, human T cell lines. The IL-2 adhesion response is blocked by wortmannin and LY294002, inhibitors of phosphatidylinositol-3 (PI-3) kinase activity. In contrast, rapamycin strongly inhibits IL-2-induced proliferation without inhibiting IL-2-induced adhesion. Herbimycin A and genestein, inhibitors of protein tyrosine kinases, inhibit cytokine-induced adhesion and mitogenesis in parallel, whereas cytochalasin E, an inhibitor of actin polymerization, almost completely blocks the adhesion response at concentrations that have little effect on mitogenesis. IL-2R ligation rapidly (<5 min) induces tyrosine phosphorylation of several proteins, the most prominent being signal transducer and activator of transcription (Stat) proteins, the p85 subunit of the PI-3 kinase, and an as yet unidentified 125-kDa protein (p125). Wortmannin, LY294002, and cytochalasin E almost completely inhibit cytokine-induced tyrosine phosphorylation of p125, whereas tyrosine phosphorylation of PI-3 kinase, Janus kinases, Stat3, Stat5, and other proteins is unaffected. In contrast, rapamycin has little effect on IL-2-induced phosphorylation of p125. Taken together, these data suggest that 1) IL-2R ligation induces homotypic adhesion through a wortmannin/LY294002-sensitive, rapamycin-resistant pathway, 2) tyrosine kinases play a critical role in cytokine-induced adhesion, and 3) adhesion, but not mitogenesis, correlates with enhanced tyrosine phosphorylation of an as yet unidentified protein of 125 kDa.
除了作为生长因子的功能外，白细胞介素-2（IL-2）还能诱导IL-2受体阳性T细胞的β2整合素依赖性同型黏附。在本研究中，我们探究了IL-2受体如何在功能和生化方面与β2整合素黏附途径相联系。经过15至20分钟的延迟期后，IL-2在抗原特异性人T细胞系中诱导β2整合素依赖性同型黏附。IL-2的黏附反应被渥曼青霉素和LY294002（磷脂酰肌醇-3（PI-3）激酶活性抑制剂）阻断。相反，雷帕霉素强烈抑制IL-2诱导的增殖，但不抑制IL-2诱导的黏附。蛋白酪氨酸激酶抑制剂赫伯霉素A和染料木黄酮同时抑制细胞因子诱导的黏附和有丝分裂，而肌动蛋白聚合抑制剂细胞松弛素E在对有丝分裂影响很小的浓度下几乎完全阻断黏附反应。IL-2受体连接迅速（<5分钟）诱导几种蛋白质的酪氨酸磷酸化，其中最显著的是信号转导和转录激活因子（Stat）蛋白、PI-3激酶的p85亚基以及一种尚未鉴定的125 kDa蛋白质（p125）。渥曼青霉素、LY294002和细胞松弛素E几乎完全抑制细胞因子诱导的p125酪氨酸磷酸化，而PI-3激酶、Janus激酶、Stat3、Stat5和其他蛋白质的酪氨酸磷酸化不受影响。相反，雷帕霉素对IL-2诱导的p125磷酸化影响很小。综上所述，这些数据表明：1）IL-2受体连接通过渥曼青霉素/LY294002敏感、雷帕霉素抗性途径诱导同型黏附；2）酪氨酸激酶在细胞因子诱导的黏附中起关键作用；3）黏附而非有丝分裂与一种尚未鉴定的125 kDa蛋白质酪氨酸磷酸化增强相关。
