Selective expression of adhesion molecules on human brain microvascular endothelial cells

Stins, Monique F.; Gilles, Floyd H.; Kim, Kwang Sik

doi:10.1016/s0165-5728(97)00036-2

Cited by 346 publications

(323 citation statements)

References 34 publications

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“…Thus, the brain endothelium likely constitutes a primary barrier to WNV neuroinvasion. Using an established endothelial cell line that exhibits the physiological characteristics of the brain endothelium (16,(22)(23)(24)(25)38) and primary brain endothelial cells, we have demonstrated that WNV-MAD78 can replicate in and traverse the brain endothelium as efficiently as WNV-NY. Our findings are consistent with reports that highly and mildly neuropathogenic strains of Semliki Forest virus replicate to equivalent levels in endothelial cells (39,40), suggesting that the capacity to cross the BBB is not always the determining factor for neuropathogenicity.…”

Section: Discussionmentioning

confidence: 97%

“…Because replication in brain endothelial cells is sufficient for transport of neuroinvasive strains of WNV across brain microvascular endothelial cells (20), we hypothesized that the decreased neuropathogenicity of WNV-MAD78 was due in part to a deficiency in replication in brain endothelial cells. Therefore, we monitored replication of WNV-NY and WNV-MAD78 in an established human brain microvascular endothelial cell line (HBMEC) that has been widely used as a model to study bacterial and parasitic neuroinvasion (16,(22)(23)(24)(25) and primary brain microvascular endothelial cells (HBMVECs) derived from normal brain cortex tissue (20,26). WNV-NY and WNV-MAD78 replicated at similar rates and to equivalent levels in both cell types, reaching peak titers between 32 and 48 h postinfection ( Fig.…”

Section: Wnv-ny and Wnv-mad78 Replicate To Similar Levels In Neuronalmentioning

confidence: 99%

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Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

Hussmann

Samuel

Kim

et al. 2013

J Virol

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The severity of West Nile virus (WNV) infection in immunocompetent animals is highly strain dependent, ranging from avirulent to highly neuropathogenic. Here, we investigate the nature of this strain-specific restriction by analyzing the replication of avirulent (WNV-MAD78) and highly virulent (WNV-NY) strains in neurons, astrocytes, and microvascular endothelial cells, which comprise the neurovascular unit within the central nervous system (CNS). We demonstrate that WNV-MAD78 replicated in and traversed brain microvascular endothelial cells as efficiently as WNV-NY. Likewise, similar levels of replication were detected in neurons. Thus, WNV-MAD78's nonneuropathogenic phenotype is not due to an intrinsic inability to replicate in key target cells within the CNS. In contrast, replication of WNV-MAD78 was delayed and reduced compared to that of WNV-NY in astrocytes. The reduced susceptibility of astrocytes to WNV-MAD78 was due to a delay in viral genome replication and an interferon-independent reduction in cell-to-cell spread. Together, our data suggest that astrocytes regulate WNV spread within the CNS and therefore are an attractive target for ameliorating WNV-induced neuropathology.

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Section: Discussionmentioning

confidence: 97%

Section: Wnv-ny and Wnv-mad78 Replicate To Similar Levels In Neuronalmentioning

confidence: 99%

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

Hussmann

Samuel

Kim

et al. 2013

J Virol

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“…For studies of brain endothelial cells we used SV-40-transformed HBMEC; HBMEC were chosen because they have been found to express features of blood-brain barrier endothelial cells and their interaction with bacterial and viral pathogens have been studied extensively (12,(21)(22)(23)(24)(25). HBMEC passages 3-5 were cultured in RPMI 1640 medium (Sigma-Aldrich), supplemented with 10% NuSerum (BD Biosciences, Mountain View, CA), 10% FBS (Sigma-Aldrich), MEM vitamins (BioWhittaker), MEM nonessential amino acids (Sigma-Aldrich), 1 mM sodium pyruvate (BioWhittaker), 2 mM L-glutamine (Sigma-Aldrich), 30 mg/ml endothelial growth supplement (Sigma-Aldrich), and 5 U/ml heparin (Sigma-Aldrich) at 37˚C in 5% CO 2 as described previously (12).…”

Section: Eukaryotic Cellsmentioning

confidence: 99%

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

Londoño

Carvajal

Strle

et al. 2011

The Journal of Immunology

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IL‐10 deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to brain hemorrhage if they are unable to clear peak bacteremia. Here we investigated the protective role of IL‐10 during relapsing‐remitting bacterial infection and explored the molecular events involved in protection of brain endothelium by IL‐10. The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL‐10 deficient mice during relapsing‐remitting infection. Human brain microvascular endothelial cells (HBMEC) upon exposure to whole bacteria or purified bacterial lipoprotein are rapidly killed by apoptosis and produced abundant pro‐inflammatory mediators but did not produce any IL‐10. HBMEC apoptosis during exposure to low number of bacteria was associated with down regulation of TNF and TNFAIP3 and upregulation of BAX. In contrast, exposure to high concentrations of purified outer membrane lipoprotein was associated with dramatic upregulation of FAS, FAS ligand, and the adaptor molecules RIPK1 and CFLAR. Exogenous IL‐10 reversed all the apoptotic signaling changes induced by whole bacteria or purified lipoprotein. The results indicate that IL‐10 prevent brain endothelial cell injury and point to a prominent role for bacterial lipoprotein mediated activation of different apoptosis pathways in this process.

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“…Primary human and mouse brain capillary endothelial cells (BCEC) were isolated, characterized and grown as described 9 and used between passages 5-14. The ␣v-positive melanoma cell line M21 and its ␣v-negative clone M21 L were kindly provided by Dr. P. Brooks (USC School of Medicine, Los Angeles, CA).…”

Section: Cell Linesmentioning

confidence: 99%

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

Taga

Suzuki

González-Gómez

et al. 2002

Intl Journal of Cancer

182

110

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Orthotopic brain tumor growth is inhibited in athymic mice by the daily systemic administration of the ␣v-integrin antagonist EMD 121974. This compound, a cyclic RGDpenta-peptide, is a potent inhibitor of angiogenesis, which induces apoptosis of growing endothelial cells through inhibition of their ␣v-integrin interaction with the matrix proteins vitronectin and tenascin. Here we show that EMD 121974 also induces apoptosis in the ␣v-integrin-expressing tumor cell lines U87 MG and DAOY by detaching them from vitronectin and tenascin, matrix proteins known to be essential for brain tumor growth and invasion. These matrix proteins are shown to be produced by the brain tumor cells in vitro and in vivo. Key words: brain tumor; xenograft; anti-angiogenesis; ␣v-integrins; apoptosisAngiogenesis, the recruitment of new blood vessels from existing capillaries, is essential for tumor growth and progression. 1 This complex process is characterized by proliferation, migration and invasion of capillary endothelial cells, as well as functional features that depend on their interactions with the surrounding extracellular matrix components. The expression of the integrin adhesion molecules ␣v␤3 and ␣v␤5 on sprouting capillary cells and their interaction with specific matrix ligands has been shown to play a key role in angiogenesis. [2][3][4] Although vitronectin is the only matrix ligand for ␣v␤5, the promiscuous ␣v␤3 receptor interacts with various matrix proteins including vitronectin, tenascin, fibronectin, fibrinogen, etc. 5 Ligand binding to these receptors through specific RGD motifs leads to complex intracellular signaling resulting in endothelial cell survival. 3,6,7 Consequently, blocking of these receptors with specific antibodies or RGD peptides results in endothelial cell apoptosis in vitro and suppression of angiogenesis in vivo, with subsequent suppression of tumor growth. 2,4 We have recently shown that the cyclic RGD pentapeptide EMD 121974, a specific ␣v-integrin antagonist, inhibited growth of brain tumor cell lines xenotransplanted into the forebrain of nu/nu mice, resulting in long-term survival. 8 In the present study, we investigated in more detail the mechanisms responsible for this growthinhibitory effect. Our data demonstrate that EMD 121974 detaches both the ␣v-integrin-expressing brain capillary and brain tumor cells from the matrix proteins vitronectin and tenascin, resulting in significant apoptosis of both cell types. We also show that the brain tumor cells produce these matrix proteins in vitro and in vivo. Furthermore, we found that only ␣v-integrin-expressing tumor cells responded in vivo to the treatment with EMD 121974. Taken together, these data suggest that EMD 121974 not only inhibits angiogenesis but is also cytotoxic for brain tumor cells. MATERIAL AND METHODS Cell linesThe human brain tumor cell lines DAOY (medulloblastoma) and U87MG (glioblastoma) were purchased from ATCC (Manassas, VA) and grown in RPMI-1640 medium with 10% FBS in 5% CO 2 at 37°C. Primary human and mouse brain capillar...

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Selective expression of adhesion molecules on human brain microvascular endothelial cells

Cited by 346 publications

References 34 publications

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

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