Interaction of vascular endothelial growth factor 165 with neuropilin-1 protects rheumatoid synoviocytes from apoptotic death by regulating Bcl-2 expression and Bax translocation
Interaction of vascular endothelial growth factor 165 with neuropilin-1 protects rheumatoid synoviocytes from apoptotic death by regulating Bcl-2 expression and Bax translocation
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DOI：
10.4049/jimmunol.177.8.5727
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发表时间：
2006-10-15
影响因子：
4.4
通讯作者：
Cho, Chul-Soo
中科院分区：
文献类型：
--
作者：
Kim, Wan-Uk;Kang, Soon Suk;Cho, Chul-Soo
类风湿关节炎(RA)滑膜细胞具有抗凋亡和表型转化的能力，这可能是由于长期暴露于包括活性氧和生长因子在内的遗传毒性刺激所致。在本研究中，我们探讨了血管内皮生长因子(165)及其受体在滑膜细胞凋亡中的作用。我们证明，在成纤维细胞样滑膜细胞中，主要的血管内皮生长因子受体是神经粘蛋白-1，而不是FMS样酪氨酸激酶-1和含有激酶插入结构域的受体。神经粘连蛋白-1在类风湿滑膜衬里层、浸润性白细胞和内皮细胞中高表达。RA滑膜细胞中神经粘连蛋白配体VEGF(165)的表达明显高于骨性关节炎滑膜细胞。重组人血管内皮细胞生长因子与其受体的结合可阻止血清饥饿或硝普钠(SNP)诱导的滑膜细胞凋亡。血管内皮细胞生长因子(165)迅速激活磷酸化Akt和磷酸化ERK活性，进而诱导类风湿滑膜细胞表达Bcl2。Akt或ERK抑制剂可阻断VEGF(165)对SNP诱导的滑膜细胞凋亡的保护作用。此外，血管内皮生长因子(165)阻断SNP诱导的Bcl2下调以及SNP诱导的Bax从胞浆到线粒体的移位。短干扰RNA下调神经粘连蛋白-1转录本可引起滑膜细胞自发性凋亡，其机制可能与Bcl2表达降低和Bax向线粒体移位增加有关。综上所述，我们的研究结果表明，血管内皮生长因子(165)与神经粘连蛋白-1的相互作用对类风湿滑膜细胞的存活至关重要，并为类风湿关节炎滑膜细胞的异常生长和治疗干预提供了重要的启示。
Rheumatoid arthritis (RA) synoviocytes are resistant to apoptosis and exhibit a transformed phenotype, Which might be caused by chronic exposure to genotoxic stimuli including reactive oxygen species and growth factors. In this study, we investigated the role of vascular endothelial growth factor(165) (VEGF(165)), a potent angiogenic factor, and its receptor in the apoptosis of synoviocytes. We demonstrated here that neuropilin-1, rather than fms-like tyrosine kinase-1 and kinase insert domain-containing receptor, is the major VEGF,ss receptor in the fibroblast-like synoviocytes. Neuropilin-1 was highly expressed in the lining layer, infiltrating leukocytes, and endothelial cells of rheumatoid synovium. The production of VEGF(165), a ligand for neuropilin, was significantly higher in the RA synoviocytes than in the osteoarthritis synoviocytes. The ligation of recombinant VEGF,ss to its receptor prevented the apoptosis of synoviocytes induced by serum starvation or sodium nitroprusside (SNP). VEGF(165) rapidly triggered phospho-Akt and phospho-ERK activity and then induced Bcl-2 expression in the rheumatoid synoviocytes. The Akt or ERK inhibitor cancelled the protective effect of VEGF(165) on SNP-induced synoviocyte apoptosis. Moreover, VEGF(165) blocks SNP-induced Bcl-2 down-regulation as well as SNP-induced Bax translocation from the cytosol to the mitochondria. The downregulation of the neuropilin-1 transcripts by short interfering RNA caused spontaneous synoviocyte apoptosis, which was associated with both the decrease in Bcl-2 expression and the increase in Bax translocation to mitochondria. Collectively, our data suggest that the interaction of VEGF(165) with neuropilin-1 is crucial to the survival of rheumatoid synoviocytes and provide important implications for the abnormal growth of synoviocytes and therapeutic intervention in RA.