Gp120-mediated cytotoxicity of human brain microvascular endothelial cells is dependent on p38 mitogen-activated protein kinase activation
Gp120-mediated cytotoxicity of human brain microvascular endothelial cells is dependent on p38 mitogen-activated protein kinase activation
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DOI：
10.1080/13550280701286531
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发表时间：
2007-01-01
影响因子：
3.2
通讯作者：
Kim, Kwang Sik
中科院分区：
文献类型：
--
作者：
Khan, Naveed Ahmed;Di Cello, Francescopaolo;Kim, Kwang Sik
血脑屏障的破坏已被证明有助于在人类免疫缺陷病毒1型（HIV-1）感染个体中流行的神经系统疾病，但与HIV-1相关的血脑屏障功能障碍的机制仍不完全清楚。使用构成血脑屏障的人脑微血管内皮细胞（HBMEC），作者确定了gp 120对HBMEC的细胞毒性作用。作者表明，gp 120诱导来自儿童的HBMEC的细胞毒性，这需要与干扰素（IFN）-γ联合治疗。IFN-γ治疗显示儿童HBMEC中趋化因子受体CCR 3和CCR 5上调。相反，从成人分离的HBMEC对gp 120介导的细胞毒性没有反应。代表CD 4和趋化因子受体结合区的gp 120肽以及CD 4抗体抑制gp 120介导的HBMEC细胞毒性。正如预期的那样，RANTES抑制M-嗜性gp 120介导的HBMEC细胞毒性，而基质细胞衍生因子（SDF）-1 α未能抑制T-嗜性gp 120介导的细胞毒性。感兴趣的是，代表非CD 4/非趋化因子受体结合区的gp 120肽抑制gp 120介导的HBMEC细胞毒性。此外，作者发现gp 120介导的HBMEC细胞毒性涉及p38丝裂原活化蛋白激酶途径。总之，这些发现表明，gp 120，在IFN-γ的存在下，可以通过MAPK途径引起血脑屏障内皮功能障碍，涉及几个gp 120-HBMEC相互作用。
Breakdown of the blood-brain barrier has been shown to contribute to neurological disorders that are prevalent in human immunodeficiency virus type 1 (HIV-1)-infected individuals, but the mechanisms involved in HIV-1 associated blood-brain barrier dysfunction remain incompletely understood. Using human brain microvascular endothelial cells (HBMECs) that constitute the blood-brain barrier, the authors determined the cytotoxic effects of gp120 on HBMECs. The authors showed that gp120 induced cytotoxicity of HBMECs derived from children, which required cotreatment with interferon (IFN)-gamma. IFN-gamma treatment exhibited up-regulation of the chemokine receptors CCR3 and CCR5 in children's HBMECs. In contrast, HBMECs isolated from adults were not responsive to gp120-mediated cytotoxicity. Peptides of gp120 representing binding regions for CD4 and chemokine receptors as well as CD4 antibody inhibited gp120-mediated cytotoxicity of HBMECs. RANTES, as expected, inhibited M-tropic gp120-mediated HBMEC cytotoxicity, whereas stromal cell-derived factor (SDF)-1 alpha failed to inhibit T-tropic gp120-mediated cytotoxicity. Of interest, gp120 peptides representing non-CD4/non-chemokine receptor binding regions inhibited gp120-mediated HBMEC cytotoxicity. In addition, the authors showed that gp120-mediated HBMEC cytotoxicity involved p38 mitogen-activated protein kinase pathway. Taken together, these findings showed that gp120, in the presence of IFN-gamma, can cause dysfunction of the blood-brain barrier endothelium via MAPK pathways involving several gp120-HBMEC interactions.