Interferon-ß Inhibits Activated Leukocyte Migration Through The Blood-Brain Barrier

Lou J, Gasche Y, Zheng L, Giroud C, Morel P, Clements J, Ythier A, Grau GE
Lab Invest 1999 Aug;79(8):1015-25
Univ, Medical Center, Dept of Anesthesiology, Pharmacology and Surgical Intensive Care, Geneva, Switzerland
PMID# 10462039; UI# 99389135

PeriVascular Leukocyte infiltration into the Central Nervous System is characteristic of Multiple Sclerosis (MS) pathology.

Interferon-beta (IFN-ß) has shown efficacy in the treatment of patients with MS, but the relevant mechanisms remain incompletely understood.

In this study the effects of IFN-ß 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 (Blood-Brain Barrier) migration capacity.

HB-MVEC prestimulated with Tumor Necrosis Factor (TNF) and IFN-gamma significantly promoted Leukocyte TransEndothelial migration.

IFN-ß 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).

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 interaction and MMP.

However IFN-ß did not interfere with the binding of Leukocytes to HB-MVEC unless IFN-ß was preincubated with Leukocytes or added to HB-MVEC at the time of stimulation.

Furthermore IFN-ß 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-ß, 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-ß in the treatment of MS patients.

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