Lopez-Ramirez, Alejandro; Fischer, Roman; Torres-Badillo, Claudia C.; Davies, Heather; Logan, Karen; Pfizenmaier, Klaus; Male, David; Sharrack, Basil and Romero, Ignacio A
(2012).
| DOI (Digital Object Identifier) Link: | http://dx.doi.org/doi:10.4049/jimmunol.1103460 |
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| Google Scholar: | Look up in Google Scholar |
Abstract
During neuroinflammation, cytokines such as TNF-α and IFN-γ secreted by activated leukocytes and/or CNS resident cells have been shown to alter the phenotype and function of brain endothelial cells (BECs) leading to blood-brain barrier breakdown. In this study, we show that the human BEC line hCMEC/D3 expresses the receptors for TNF-α, TNF receptor 1 and TNF receptor 2, and for IFN-γ. BEC activation with TNF-α alone or in combination with IFN-γ induced endothelial leakage of paracellular tracers. At high cytokine concentrations (10 and 100 ng/ml), this effect was associated with caspase-3/7 activation and apoptotic cell death as evidenced by annexin V staining and DNA fragmentation (TUNEL) assays. In addition, inhibition of JNK and protein kinase C activation at these doses partially prevented activation of caspase-3/7, although only JNK inhibition was partially able to prevent the increase in BEC paracellular permeability induced by cytokines. By contrast, lower cytokine concentrations (1 ng/ml) also led to effector caspase activation, increased paracellular flux, and redistribution of zonula occludens-1 and VE-cadherin but failed to induce apoptosis. Under these conditions, specific caspase-3 and caspase-9, but not caspase-8, inhibitors partially blocked cytokine-induced disruption of tight and adherens junctions and BEC paracellular permeability. Our results suggest that the concentration of cytokines in the CNS endothelial microenvironment determines the extent of caspase-mediated barrier permeability changes, which may be generalized as a result of apoptosis or more subtle as a result of alterations in the organization of junctional complex molecules.
| Item Type: | Journal Article |
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| Copyright Holders: | 2012 The American Association of Immunologists, Inc |
| ISSN: | 1550-6606 |
| Academic Unit/Department: | Science > Life, Health and Chemical Sciences Science |
| Related URLs: | |
| Item ID: | 34217 |
| Depositing User: | Ignacio A Romero |
| Date Deposited: | 21 Aug 2012 08:08 |
| Last Modified: | 14 Nov 2012 11:56 |
| URI: | http://oro.open.ac.uk/id/eprint/34217 |
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