HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood-brain barrier: modulatory effects of STAT1 signaling.
HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood-brain barrier: modulatory effects of STAT1 signaling.
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DOI：
10.1016/j.mvr.2008.11.003
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发表时间：
2009-03
影响因子：
3.1
通讯作者：
Kanmogne, Georgette D.
中科院分区：
文献类型：
--
作者：
Yang, Bo;Akhter, Sidra;Chaudhuri, Anathbandhu;Kanmogne, Georgette D.
在HIV/AIDS期间，神经炎性活动如何影响导致血脑屏障(BBB)损伤的信号通路目前尚不清楚。我们先前的工作表明，HIV-1暴露可激活人脑微血管内皮细胞(HBMEC)中的促炎基因，并表明这些基因与Janus Kinase(JAK)/信号转导和转录激活因子(STAT)途径有关。在这里，我们报道了HIV-1gp120蛋白激活STAT1，并诱导HBMEC分泌IL-6和IL-8。IL-6、IL-8和gp120可增加体外BBB模型中单核细胞的黏附和迁移。STAT1抑制剂氟达拉滨可阻止gp120诱导的IL-6和IL-8的分泌。STAT1、丝裂原活化蛋白激酶(MEK)(PD98059)和磷脂酰肌醇3激酶(PI3K)(LY294002)的抑制剂可阻断gp120诱导的STAT1激活，并显著降低IL-8、IL-6和gp120诱导的单核细胞跨体外BBB模型的黏附和迁移。这些数据支持这样的观点，即STAT1在gp120诱导的炎症和与病毒感染相关的BBB功能障碍中发挥重要作用。结果还表明，在gp120诱导的血脑屏障功能障碍中，STAT1、MEK和PI3K信号通路之间存在串扰。抑制STAT1的激活可以提供一种独特的治疗策略来减少HIV/AIDS的神经炎症和BBB功能障碍。
How neuroinflammatory activities affect signaling pathways leading to blood-brain barrier (BBB) injury during HIV/AIDS are currently unknown. Our previous work demonstrated that HIV-1 exposure activates pro-inflammatory genes in human brain microvascular endothelial cells (HBMEC) and showed that these genes are linked to the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Here, we report that HIV-1 gp120 protein activated STAT1 and induced interleukin (IL)-6 and IL-8 secretion in HBMEC. IL-6, IL-8, and gp120 increased monocyte adhesion and migration across in vitro BBB models. The STAT1 inhibitor, fludarabine, prevented gp120-induced IL-6 and IL-8 secretion. Inhibitors of STAT1, mitogen activated protein kinase kinase (MEK) (PD98059), and phosphatidyl inositol 3 kinase (PI3K) (LY294002), blocked gp120-induced STAT1 activation and significantly diminished IL-8-, IL-6-, and gp120-induced monocyte adhesion and migration across in vitro BBB models. These data support the notion that STAT1 plays an important role in gp120-induced inflammation and BBB dysfunction associated with viral infection. Results also suggest crosstalk between STAT1, MEK, and PI3K pathways in gp120-induced BBB dysfunction. Inhibition of STAT1 activation could provide a unique therapeutic strategy to decrease neuroinflammation and BBB dysfunction in HIV/AIDS.
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影响因子：
5.4
作者：
Capobianchi, MR;Barresi, C;Dianzani, F
通讯作者：
Dianzani, F
影响因子：
2.4
作者：
Langford, D;Hurford, R;Masliah, E
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Masliah, E
影响因子：
5.4
作者：
Cervasi, B.;Paiardini, A.;Magnani, M.
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Magnani, M.
人类免疫缺陷病毒对重组刺激因子1处理的单核细胞的有效分离和传播。
影响因子：
15.3
作者：
GENDELMAN, HE;ORENSTEIN, JM;MARTIN, MA;FERRUA, C;MITRA, R;PHIPPS, T;WAHL, LA;LANE, HC;FAUCI, AS;BURKE, DS;SKILLMAN, D;MELTZER, MS
通讯作者：
MELTZER, MS
影响因子：
11.4
作者：
Kovarik, P;Mangold, M;Decker, T
通讯作者：
Decker, T