Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120
Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120
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DOI：
10.1186/1471-2202-6-8
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发表时间：
2005-02-02
期刊：
影响因子：
2.4
通讯作者：
Masliah, E
中科院分区：
文献类型：
--
作者：
Langford, D;Hurford, R;Masliah, E
背景资料：血脑屏障（BBB）是中枢神经系统（CNS）抵御循环病原体（如HIV）的第一道防线。细胞毒性HIV蛋白gp 120破坏BBB的内皮细胞，从而损害其完整性，这可能导致HIV感染的细胞迁移到脑中。成纤维细胞生长因子2（FGF 2）主要由星形胶质细胞产生，促进内皮细胞适应性和血管生成。我们假设用FGF 2处理人脐静脉内皮细胞（HUVEC）会通过内皮细胞存活信号转导保护细胞免受gp 120介导的毒性。结果：HUVEC暴露于gp 120导致剂量和时间依赖性细胞死亡;而用FGF 2预处理内皮细胞保护细胞免受gp 120血管毒性。用FGF 2处理HUVEC导致细胞外调节激酶（ERK）的剂量和时间依赖性活化，对磷酸肌醇3激酶（PI 3 K）和蛋白激酶B（PKB）（也称为AKT）具有中等影响，但对糖原合成酶激酶3（GSK 3 β）活性没有影响。使用药理学方法，基因转移和激酶活性测定，我们表明，FGF 2介导的血管保护对gp 120的毒性是由ERK，PI 3 KAKT和PKC信号通路之间的串扰调节：总之，这些结果表明，FGF 2可能发挥重要作用，在维持BBB的完整性，在HIV相关的脑内皮细胞损伤的进展。
Background: The blood brain barrier ( BBB) is the first line of defence of the central nervous system ( CNS) against circulating pathogens, such as HIV. The cytotoxic HIV protein, gp120, damages endothelial cells of the BBB, thereby compromising its integrity, which may lead to migration of HIV- infected cells into the brain. Fibroblast growth factor 2 ( FGF2), produced primarily by astrocytes, promotes endothelial cell fitness and angiogenesis. We hypothesized that treatment of human umbilical vein endothelial cells ( HUVEC) with FGF2 would protect the cells from gp120- mediated toxicity via endothelial cell survival signalling.Results: Exposure of HUVEC to gp120 resulted in dose- and time- dependent cell death; whereas, pre- treatment of endothelial cells with FGF2 protected cells from gp120 angiotoxicity. Treatment of HUVEC with FGF2 resulted in dose- and time- dependent activation of the extracellular regulated kinase ( ERK), with moderate effects on phosphoinositol 3 kinase ( PI3K) and protein kinase B ( PKB), also known as AKT, but no effects on glycogen synthase kinase 3 ( GSK3beta) activity. Using pharmacological approaches, gene transfer and kinase activity assays, we show that FGF2mediated angioprotection against gp120 toxicity is regulated by crosstalk among the ERK, PI3KAKT and PKC signalling pathways.Conclusions: Taken together, these results suggest that FGF2 may play a significant role in maintaining the integrity of the BBB during the progress of HIV associated cerebral endothelial cell damage.