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Interferon-beta inhibits activated leukocyte migration through human brain microvascular endothelial cell monolayer

Clements, J
Grau, G E
Published in Laboratory investigation. 1999, vol. 79, no. 8, p. 1015-25
Abstract Perivascular leukocyte infiltration into the central nervous system is characteristic of multiple sclerosis (MS) pathology. Interferon-beta (IFN-beta) has shown efficacy in the treatment of patients with MS, but the relevant mechanisms remain incompletely understood. In this study the effects of IFN-beta on leukocyte transendothelial migration were investigated using cells relevant to MS pathogenesis, namely human brain microvascular endothelial cells (HB-MVEC). Activated, but not resting leukocytes exhibited a high transendothelial migration capacity. HB-MVEC prestimulated with tumor necrosis factor (TNF) and IFN-gamma significantly promoted leukocyte transendothelial migration. IFN-beta inhibited the activated leukocyte transendothelial migration on TNF/IFN-gamma-activated HB-MVEC in a dose-dependent manner. A matrix metalloproteinase (MMP) inhibitor and monoclonal antibodies to lymphocyte function antigen-1 (LFA-1) or intercellular adhesion molecule-1 (ICAM-1), but not to very late antigen-4 or to vascular cell adhesion molecule-1 significantly inhibited the transendothelial migration of stimulated leukocytes, suggesting that this phenomenon involves the LFA-1/ICAM-1 interaction and MMP. However IFN-beta did not interfere with the binding of leukocytes to HB-MVEC unless IFN-beta was preincubated with leukocytes or added to HB-MVEC at the time of stimulation. Furthermore IFN-beta did not modulate the expression of adhesion molecules on either stimulated leukocytes or activated HB-MVEC, but partially reduced TNF and interleukin-1 production from stimulated leukocytes during coculture with HB-MVEC. Interestingly, in the presence of IFN-beta, a significant down-regulation of MMP-9 release from stimulated leukocytes was found, especially for the activated form of MMP-9. These results indicate that inhibition of leukocyte transendothelial migration is an important mechanism accounting for the beneficial effects of IFN-beta in the treatment MS patients.
Keywords Brain/blood supplyCell Adhesion/drug effectsCell Movement/drug effectsCells, CulturedEndothelium, Vascular/cytologyHumansIntegrin alpha4beta1Integrins/physiologyIntercellular Adhesion Molecule-1/physiologyInterferon-beta/pharmacologyInterferon-gamma/pharmacologyInterleukin-1/secretionLeukocytes/drug effects/physiologyMatrix Metalloproteinase 9Matrix Metalloproteinase InhibitorsMicrocirculation/cytologyMultiple Sclerosis/etiology/therapyReceptors, Lymphocyte Homing/physiologyTumor Necrosis Factor-alpha/secretionVascular Cell Adhesion Molecule-1/physiology
PMID: 10462039
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Research groups Chirurgie viscérale (104)
Chirurgie viscérale (HUG)
Groupe Gasche Yvan (Soins intensifs) (501)
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LOU, Jinning et al. Interferon-beta inhibits activated leukocyte migration through human brain microvascular endothelial cell monolayer. In: Laboratory investigation, 1999, vol. 79, n° 8, p. 1015-25. https://archive-ouverte.unige.ch/unige:72856

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Deposited on : 2015-05-28

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