HIV-1 Tat-mediated induction of platelet-derived growth factor in astrocytes: role of early growth response gene 1.
HIV-1 Tat-mediated induction of platelet-derived growth factor in astrocytes: role of early growth response gene 1.
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DOI：
10.4049/jimmunol.1002235
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发表时间：
2011-04-01
期刊：
影响因子：
--
通讯作者：
Buch S
中科院分区：
文献类型：
--
作者：
Bethel-Brown C;Yao H;Callen S;Lee YH;Dash PK;Kumar A;Buch S
据估计，艾滋病毒相关神经疾病(HAND)影响到近60%的艾滋病毒感染者。人类免疫缺陷病毒脑炎(HIVE)是最严重的手部疾病，通常以神经胶质细胞激活、细胞因子/趋化因子失调、神经元损伤和丢失为特征。然而，蜂窝病毒的严重程度与神经胶质细胞激活的相关性更好，而不是病毒载量。使用猕猴模型，已经证明猴免疫缺陷病毒脑炎(SIVE)与大脑中有丝分裂原血小板衍生生长因子B(PDGF-B)链的表达增加有关。本研究旨在探讨PDGF-B链在HIV相关星形胶质细胞激活和增殖中的作用。具体地说，这里的数据表明，大鼠和人类星形胶质细胞暴露于HIV-1蛋白TAT后，在mRNA和蛋白水平上都能诱导PDGF的产生。此外，PDGF-BB的诱导受ERK1/2和JNK信号通路以及下游转录因子早期生长反应1(Egr-1)的调节。染色质免疫沉淀(ChIP)检测表明Egr-1与PDGF-B启动子结合。反过来，星形胶质细胞暴露于血小板衍生生长因子BB后，其增殖和促炎细胞因子单核细胞趋化蛋白-1和白介素1β的释放均增加。由于星形胶质细胞增多症与疾病的严重程度有关，了解PDGF-BB对其的调节有助于开发针对HAND的治疗干预策略。
HIV-associated neurological disorders (HAND) are estimated to affect almost 60% of HIV infected individuals. HIV-encephalitis (HIVE), the pathological correlate of the most severe form of HAND is often characterized by glial activation, cytokine/chemokine dysregulation, and neuronal damage and loss. However, the severity of HIVE correlates better with glial activation rather than viral load. Using the macaque model, it has been demonstrated that simian immunodeficiency virus encephalitis (SIVE) correlates with increased expression of the mitogen platelet-derived growth factor-B (PDGF-B) chain in the brain. The present study was aimed at exploring the role of PDGF-B chain in HIV-associated activation and proliferation of astrocytes. Specifically, the data herein demonstrate that exposure of rat and human astrocytes to the HIV-1 protein, Tat resulted in the induction of PDGF at both the mRNA and protein levels. Furthermore, PDGF-BB induction was regulated by activation of ERK1/2 and JNK signaling pathways and the downstream transcription factor, early growth response 1(Egr-1). Chromatin immunoprecipitation (ChIP) assays demonstrated binding of Egr-1 to the PDGF-B promoter. Exposure of astrocytes to PDGF-BB, in turn, led to both increased proliferation and release of pro-inflammatory cytokines MCP-1 and IL-1β. Since astrogliosis is linked to disease severity, understanding its regulation by PDGF-BB could aid in the development of therapeutic intervention strategies for HAND.
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