Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by luminal microvessel IL-6 and GM-CSF.
Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by luminal microvessel IL-6 and GM-CSF.
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DOI：
10.1186/1742-2094-8-167
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发表时间：
2011-11-30
影响因子：
9.3
通讯作者：
Banks WA
中科院分区：
文献类型：
--
作者：
Dohgu S;Fleegal-DeMotta MA;Banks WA
细胞因子/趋化因子水平升高有助于增加人类免疫缺陷病毒1型（HIV-1）的神经侵袭。以前的工作表明，脂多糖（LPS），这是存在于患者的血浆中的HIV-1，增强跨血脑屏障（BBB）通过激活p38丝裂原活化蛋白激酶（MAPK）信号转导在脑微血管内皮细胞（BMEC）的HIV-1的跨细胞运输。在此，我们发现LPS（100 μg/mL，4小时）选择性地增加BMEC释放白细胞介素（IL）-6和粒细胞-巨噬细胞集落刺激因子（GM-CSF）。增强的HIV-1运输诱导的管腔LPS被中和的治疗与管腔，但不是与管腔外，抗体IL-6和GM-CSF，而不影响细胞旁的渗透性所测量的跨内皮电阻（TEER）。IL-6或GM-CSF也可增加HIV-1的腔内转运，但对腔外转运无影响。MAPK激酶（MEK）1/2抑制剂U 0126和p38 MAPK抑制剂SB 203580可降低LPS诱导的IL-6和GM-CSF的释放。这些结果表明，p44/42和p38 MAPK信号通路介导了LPS增强的IL-6和GM-CSF的释放。反过来，这些细胞因子作用于BMEC的腔表面，以增强HIV-1的跨细胞转运，而不依赖于对细胞旁通透性的作用。
Elevated levels of cytokines/chemokines contribute to increased neuroinvasion of human immunodeficiency virus type 1 (HIV-1). Previous work showed that lipopolysaccharide (LPS), which is present in the plasma of patients with HIV-1, enhanced transcellular transport of HIV-1 across the blood-brain barrier (BBB) through the activation of p38 mitogen-activated protein kinase (MAPK) signaling in brain microvascular endothelial cells (BMECs). Here, we found that LPS (100 μg/mL, 4 hr) selectively increased interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) release from BMECs. The enhancement of HIV-1 transport induced by luminal LPS was neutralized by treatment with luminal, but not with abluminal, antibodies to IL-6 and GM-CSF without affecting paracellular permeability as measured by transendothelial electrical resistance (TEER). Luminal, but not abluminal, IL-6 or GM-CSF also increased HIV-1 transport. U0126 (MAPK kinase (MEK)1/2 inhibitor) and SB203580 (p38 MAPK inhibitor) decreased the LPS-enhanced release of IL-6 and GM-CSF. These results show that p44/42 and p38 MAPK signaling pathways mediate the LPS-enhanced release of IL-6 and GM-CSF. These cytokines, in turn, act at the luminal surface of the BMEC to enhance the transcellular transport of HIV-1 independently of actions on paracellular permeability.
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