Tumour necrosis factor α enhances CCL2 and ICAM-1 expression in peripheral nerve microvascular endoneurial endothelial cells.
Tumour necrosis factor α enhances CCL2 and ICAM-1 expression in peripheral nerve microvascular endoneurial endothelial cells.
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DOI：
10.1042/an20120048
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发表时间：
2013-02-06
期刊：
影响因子：
4.7
通讯作者：
Stubbs EB Jr
中科院分区：
文献类型：
--
作者：
Langert KA;Von Zee CL;Stubbs EB Jr
自体反应性白细胞的募集和运输穿过BNB（血神经屏障）是GBS（格林-巴利综合征）的早期病理损伤，GBS是PNS（外周神经系统）的侵袭性自身免疫性疾病。尽管GBS的病因和发病机制尚不清楚，但据报道，促炎细胞因子（包括TNFα（肿瘤坏死因子α））在GBS病程早期升高，并可能通过激活BNB引发神经损伤。以前，我们报道，破坏白细胞运输在体内治疗衰减过程中建立的动物模型GBS。在此，从大鼠坐骨神经收获形成BNB的PNMEC（外周神经微血管内皮细胞），通过SV 40（猿猴病毒40）大T抗原转导使其永生化，随后用TNFα激发。测定CCL 2（趋化因子配体2）和ICAM-1（细胞间粘附分子1）表达的相对变化。我们报道TNFα可显著增加CCL 2和ICAM-1 mRNA和蛋白含量，并促进永生化和原代PNMEC培养物中功能性CCL 2的分泌，且呈剂量和时间依赖性。TNFα介导的CCL 2分泌在体外促进表达CCR 2的THP-1单核细胞的跨内皮迁移。在自身免疫性疾病（包括GBS）中，对TNFα应答的CCL 2和ICAM-1表达增加可能促进自身反应性白细胞通过BNB的募集和运输。
Recruitment and trafficking of autoreactive leucocytes across the BNB (blood–nerve barrier) is an early pathological insult in GBS (Guillain-Barré syndrome), an aggressive autoimmune disorder of the PNS (peripheral nervous system). Whereas the aetiology and pathogenesis of GBS remain unclear, pro-inflammatory cytokines, including TNFα (tumour necrosis factor α), are reported to be elevated early in the course of GBS and may initiate nerve injury by activating the BNB. Previously, we reported that disrupting leucocyte trafficking in vivo therapeutically attenuates the course of an established animal model of GBS. Here, PNMECs (peripheral nerve microvascular endothelial cells) that form the BNB were harvested from rat sciatic nerves, immortalized by SV40 (simian virus 40) large T antigen transduction and subsequently challenged with TNFα. Relative changes in CCL2 (chemokine ligand 2) and ICAM-1 (intercellular adhesion molecule 1) expression were determined. We report that TNFα elicits marked dose- and time-dependent increases in CCL2 and ICAM-1 mRNA and protein content and promotes secretion of functional CCL2 from immortalized and primary PNMEC cultures. TNFα-mediated secretion of CCL2 promotes, in vitro, the transendothelial migration of CCR2-expressing THP-1 monocytes. Increased CCL2 and ICAM-1 expression in response to TNFα may facilitate recruitment and trafficking of autoreactive leucocytes across the BNB in autoimmune disorders, including GBS.