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

Perivascular leukocyte infiltration into the central nervous system is char acteristic 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 tra nsendothelial migration capacity. HB-MVEC prestimulated with tumor necrosis factor (TNF) and IFN-gamma significantly promoted leukocyte transendotheli al migration. IFN-beta inhibited the activated leukocyte transendothelial m igration on TNF/IFN-gamma-activated HB-MVEC in a dose-dependent manner. A m atrix metalloproteinase (MMP) inhibitor and monoclonal antibodies to lympho cyte 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 leukoc ytes, 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 ai:the time of stimulation. Furthermore IFN-beta did not modulate the expression of adhesion molecules on either stimulated leukocytes or activa ted HB-MVEC, but partially reduced TNF and interleukin-l production from st imulated leukocytes during coculture with HB-MVEC. Interestingly, in the pr esence of IFN-beta, a significant down-regulation of MMP-9 release from sti mulated leukocytes was found, especially for the activated form of MMP-9. T hese results indicate that inhibition of leukocyte transendothelial migrati on is an important mechanism accounting for the beneficial effects of IFN-b eta in the treatment MS patients.