title: Interferon-beta inhibits activated leukocyte migration through human brain microvascular endothelial cell monolayer.
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.
authors.affiliation: Department of Anesthesiology, Pharmacology and Surgical Intensive Care, University Medical Center, Geneva, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Lou
authors.forename: Y
authors.initials: Y
authors.lastname: Gasche
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.forename: C
authors.initials: C
authors.lastname: Giroud
authors.forename: P
authors.initials: P
authors.lastname: Morel
authors.forename: J
authors.initials: J
authors.lastname: Clements
authors.forename: A
authors.initials: A
authors.lastname: Ythier
authors.forename: G E
authors.initials: GE
authors.lastname: Grau
mesh_terms: D001921:Brain / Q000098:blood supply*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008833:Microcirculation / Q000166:cytology; D009103:Multiple Sclerosis / Q000209:etiology / Q000628:therapy*; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
chemical_list: D039041:Integrin alpha4beta1; D016023:Integrins; D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9