Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway
Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway
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DOI：
10.1016/j.expneurol.2007.12.028
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发表时间：
2008-04-01
影响因子：
5.3
通讯作者：
Banks, William A.
中科院分区：
文献类型：
--
作者：
Dohgu, Shinya;Banks, William A.
HIV-1感染晚期的慢性全身炎症可增加感染单核细胞和游离病毒的神经侵袭，导致AIDS患者神经系统疾病加重。我们以前表明，外周注射脂多糖（LPS）增强了HIV-1病毒蛋白gp 120穿过血脑屏障（BBB）的摄取。脑微血管内皮细胞是LPS作用的靶细胞。在这里，我们调查是否LPS和血脑屏障之间的直接相互作用也影响HIV-1运输使用原代小鼠脑微血管内皮细胞（BMEC）。LPS产生的剂量（1-100 μ g/mL）和时间（0.5-4小时）依赖性增加的HIV-1的运输和减少跨内皮电阻（TEER）。而吲哚美辛（环氧合酶抑制剂）和L-NAME（NO合成酶抑制剂）不影响LPS诱导的HIV-1转运或TEER的变化，戊茶碱（TNF-α抑制剂）减弱LPS诱导的TEER的降低，但不影响LPS诱导的HIV-1转运增加。LPS还增加p44/42 MAPK和p38 MAPK的磷酸化，但不增加JNK的磷酸化。U 0126（p44/42 MAPK抑制剂）和SP 600125（JNK抑制剂）不抑制LPS诱导的HIV-1转运增加，尽管U 0126减弱了TEER的降低。SB 203580（p38 MAPK抑制剂）抑制LPS诱导的HIV-1转运增加，而不影响TEER。因此，LPS增强的HIV-1转运与TEER的变化无关，因此归因于HIV-1跨BBB的跨细胞转运增加。这些结果表明，LPS通过由BMEC中的p38 MAPK磷酸化介导的途径增加HIV-1跨BBB的跨细胞转运。爱思唯尔公司出版
Chronic systemic inflammation in the late stage of human immunodeficiency virus type-1 (HTV-1) infection could increase neuroinvasion of infected monocytes and cell-free virus, causing an aggravation of neurological disorders in AIDS patients. We previously showed that the peripheral administration of lipopolysaccharide (LPS) enhanced the uptake across the blood-brain barrier (BBB) of the HIV-1 viral protein gp120. Brain microvessel endothelial cells are targets of LPS. Here, we investigated whether the direct interaction between LPS and the BBB also affected HIV-1 transport using primary mouse brain microvessel endothelial cells (BMECs). LPS produced a dose (1-100 mu g/mL)- and time (0.5-4 h)dependent increase in HIV-1 transport and a decrease in transendothelial electrical resistance (TEER). Whereas indomethacin (cyclooxygenase inhibitor) and L-NAME (NO synthase inhibitor) did not affect the LPS-induced changes in HIV-1 transport or TEER, pentoxifylline (TNF-alpha inhibitor) attenuated the decrease in TEER induced by LPS, but not the LPS-induced increase in HIV-1 transport. LPS also increased the phosphorylation of p44/42 MAPK and p38 MAPK but not that of JNK. U0126 (p44/42 MAPK inhibitor) and SP600125 (JNK inhibitor) did not inhibit the LPS-induced increase in HIV-1 transport although U0126 attenuated the reduction in TEER. SB203580 (p38 MAPK inhibitor) inhibited the LPS-induced increase in HIV-1 transport without affecting TEER. Thus, LPS-enhanced HIV-1 transport is independent of changes in TEER and so is attributed to increased transcellular trafficking of HIV-1 across the BBB. These results show that LPS increases HIV-1 transcellular transport across the BBB by a pathway that is mediated by p38 MAPK phosphorylation in BMECs. Published by Elsevier Inc.