Gp120 activates children's brain endothelial cells via CD4

Stins, Monique F.; Shen, Yamin; Huang, Sheng; Gilles, Floyd H.; Kalra, Vijay K.; Kim, Kwang Sik

doi:10.1080/13550280152058780

Cited by 32 publications

(15 citation statements)

References 54 publications

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“…Cells were grown in DMEM/F12 plus FBS (10%) and penicillin/streptomycin (1%), as published (14, 23). Human brain microvascular endothelial cells (isolate # 4 or HBMEC-4) were obtained following isolation of brain capillaries and their culturing as previously described (24, 25), and used at early passages. Human astrocytes were purchased from Lonza (Lonza Group Ltd., Basel, Switzerland), and grown in media supplemented with AGM Bulletkit for astrocytes (astrocyte growth media, cat # CC-1423).…”

Section: Methodsmentioning

confidence: 99%

Heparanase-Induced GEF-H1 Signaling Regulates the Cytoskeletal Dynamics of Brain Metastatic Breast Cancer Cells

Ridgway

Wetzel

Ngo

et al. 2012

Molecular Cancer Research

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Heparanase (HPSE) is the only mammalian endoglycosidase which has been widely implicated in cancer because of its capability to degrade heparan sulfate chains (HS) of HS proteoglycans (HSPGs). Specifically, the cell surface HSPG syndecans 1 and 4 (SDC1 and SDC4) are modulators of growth factor action and SDC4 is implicated in cell adhesion as a key member of focal adhesion complexes. We hypothesized that extracellular heparanase modulates brain metastatic breast cancer (BMBC) cell invasiveness by affecting cytoskeletal dynamics, SDC4 carboxy terminal-associated proteins, and downstream targets. We used two independently-derived human BMBC cell systems (MB-231BR, MB-231BR3), which possess distinct cellular morphologies and properties. Highly aggressive spindle-shaped 231BR3 cells changed to a round-cell morphology associated with expression of the small GTPase guanine nucleotide exchange factor-H1 (GEF-H1). We demonstrated that GEF-H1 is a new component of the SDC4 signaling complex in BMBC cells. Treatment with HPSE resulted in regulation of the SDC4/protein kinase Cα axis while maintaining a constitutive GEF-H1 level. Third, GEF-H1 knockdown followed by cell exposure to HPSE caused a significant regulation of activities of Rac1 and RhoA, which are GEF-H1 targets and fundamental effectors in cell plasticity control. Fourth, L-HPSE augmented expression of β1 Integrin in BMBC cells and of vascular cell adhesion molecule 1 (VCAM1; the major β1 Integrin receptor) in human brain microvascular endothelial cells. Finally, using a newly developed blood-brain barrier in vitro model, we show that BMBC cell transmigration was significantly reduced in GEF-H1 knockdown cells. These findings implicate heparanase in mechanisms of cytoskeletal dynamics and in the cross-talk between tumor cells and vascular brain endothelium. They are of relevance because they elucidate molecular events in the initial steps leading to BMBC onset and capturing distinct roles of latent and active HPSE in the brain microenvironment.

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Section: Methodsmentioning

confidence: 99%

Heparanase-Induced GEF-H1 Signaling Regulates the Cytoskeletal Dynamics of Brain Metastatic Breast Cancer Cells

Ridgway

Wetzel

Ngo

et al. 2012

Molecular Cancer Research

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“…Removal of gp120 resulted in complete restoration of TEER and significant improvement in permeability. Exposure of HBMECs to gp120 in vitro resulted in increased expression of adhesion molecules (ICAM and VCAM), damage to the barrier and a consequent increase in monocyte migration across the monolayer of endothelial cells [45]. There was a dose dependent increase in cytotoxicity of HBMECs when exposed to recombinant gp120, and gp120-mediated HBMEC cytotoxicity has been shown to involve the p38 mitogen-activated protein (MAP) kinase pathway [46].…”

Section: Cns Invasion: Disruption Of the Blood Brain Barriermentioning

confidence: 99%

Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND)

2014

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As the HIV-1 epidemic enters its fourth decade, HIV-1 associated neurological disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of anti-retroviral therapy. Advancing age and increased life expectancy of the HIV-1 infected population have been shown to increase the risk of cognitive dysfunction. Over the past 10 years, there has been a significant progress in our understanding of the mechanisms and the risk factors involved in the development of HAND. Key events that lead up to neuronal damage in HIV-1 infected individuals can be categorized based on the interaction of HIV-1 with the various cell types, including but not limited to macrophages, brain endothelial cells, microglia, astrocytes and the neurons. This review attempts to decipher these interactions, beginning with HIV-1 infection of macrophages and ultimately resulting in the release of neurotoxic viral and host products. These include: interaction with endothelial cells, resulting in the impairment of the blood brain barrier; interaction with the astrocytes, leading to metabolic and neurotransmitter imbalance; interactions with resident immune cells in the brain, leading to release of toxic cytokines and chemokines. We also review the mechanisms underlying neuronal damage caused by the factors mentioned above. We have attempted to bring together recent findings in these areas to help appreciate the viral and host factors that bring about neurological dysfunction. In addition, we review host factors and viral genotypic differences that affect phenotypic pathological outcomes, as well as recent advances in treatment options to specifically address the neurotoxic mechanisms in play.

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“…Leukocyte recruitment into the CNS plays a crucial role in the inflammatory response during Blood-brain barrier (BBB)1017. In order to exclude the possibility that the monocyte (leukocytes) migration elicited was due to destruction of HBMECs, the integrity of the monolayer(leukocytes) was confirmed by microscopy.…”

Section: Resultsmentioning

confidence: 99%

“…HBMECs were isolated and cultured as described previously1743. HBMECs were routinely cultured in RPMI 1640 medium (Mediatech, Herndon, VA) containing 10% heat inactivated fetal bovine serum, 10% Nu-serum, 2 mM glutamine, 1 mM sodium pyruvate, essential amino acids, vitamins, penicillin G (50 mg/ml) and streptomycin (100 mg/ml) at 37 °C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

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Alpha7 nicotinic acetylcholine receptor is required for amyloid pathology in brain endothelial cells induced by Glycoprotein 120, methamphetamine and nicotine

Liu

et al. 2017

Sci Rep

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One of the most challenging issues in HIV-associated neurocognitive disorders (HAND) caused by HIV-1 virotoxins and drug abuse is the lack of understanding the underlying mechanisms that are commonly associated with disorders of the blood-brain barrier (BBB), which mainly consists of brain microvascular endothelial cells (BMEC). Here, we hypothesized that Glycoprotein 120 (gp120), methamphetamine (METH) and nicotine (NT) can enhance amyloid-beta (Aβ) accumulation in BMEC through Alpha7 nicotinic acetylcholine receptor (α7 nAChR). Both in vitro (human BMEC) (HBMEC) and in vivo (mice) models of BBB were used to dissect the role of α7 nAChR in up-regulation of Aβ induced by gp120, METH and NT. Aβ release from and transport across HBMEC were significantly increased by these factors. Methyllycaconitine (MLA), an antagonist of α7 nAChR, could efficiently block these pathogenic effects. Furthermore, our animal data showed that these factors could significantly increase the levels of Aβ, Tau and Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in mouse cerebrospinal fluid (CSF) and Aβ in the mouse brains. These pathogenicities were significantly reduced by MLA, suggesting that α7 nAChR may play an important role in neuropathology caused by gp120, METH and NT, which are the major pathogenic factors contributing to the pathogenesis of HAND.

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Gp120 activates children's brain endothelial cells via CD4

Cited by 32 publications

References 54 publications

Heparanase-Induced GEF-H1 Signaling Regulates the Cytoskeletal Dynamics of Brain Metastatic Breast Cancer Cells

Heparanase-Induced GEF-H1 Signaling Regulates the Cytoskeletal Dynamics of Brain Metastatic Breast Cancer Cells

Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND)

Alpha7 nicotinic acetylcholine receptor is required for amyloid pathology in brain endothelial cells induced by Glycoprotein 120, methamphetamine and nicotine

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