NDLI: Role of caspases in cytokine-induced barrier breakdown in human brain endothelial cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Pfizenmaier, Klaus Davies, Heather A. Male, David K. Lopez-Ramirez, M. Alejandro Torres-Badillo, Claudia C. Fischer, Roman Romero, Ignacio A. Sharrack, Basil Logan, Karen
Description	Country affiliation: United kingdom Author Affiliation: Lopez-Ramirez MA ( Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes MK7 6AA, UK.)
Abstract	During neuroinflammation, cytokines such as TNF- and IFN-Î³ 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- , TNF receptor 1 and TNF receptor 2, and for IFN-Î³. BEC activation with TNF- alone or in combination with IFN-Î³ 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.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	6
Volume Number	189
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2012-09-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Blood-brain Barrier Enzymology Immunology Brain Cytokines Physiology Endothelium, Vascular Pathology Cell Line Inflammation Mediators Metabolism Interferon-gamma Microcirculation Receptors, Interferon Biosynthesis Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type Ii Subcellular Fractions Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in