Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells

• Published in: Annals of the rheumatic diseases 2004-12, Vol.63 (12), p.1632-1637
• Main Authors: Grisar, J, Aringer, M, Köller, M D, Stummvoll, G H, Eselböck, D, Zwölfer, B, Steiner, C W, Zierhut, B, Wagner, L, Pietschmann, P, Smolen, J S
• Format: Article
• Language: English
• Subjects: A77 1726; A771 726; Antirheumatic Agents - antagonists & inhibitors; Antirheumatic Agents - pharmacology; Biological and medical sciences; Biopsy; BND; Bones, joints and connective tissue. Antiinflammatory agents; bound; Cell adhesion & migration; Cell Adhesion - drug effects; Cell division; Cell Movement - drug effects; Cells, Cultured; Chemotaxis, Leukocyte - drug effects; Collagen; Cytokines; Dex; dexamethasone; DHODH; dihydro-orotate dehydrogenase; disease modifying antirheumatic drug; DMARD; endothelial cell(s); endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Enzymes; Evacuations & rescues; Experiments; Extended Report; Flow Cytometry; Humans; Hyaluronic Acid - metabolism; Isoxazoles - antagonists & inhibitors; Isoxazoles - pharmacology; LEF-M; leflunomide; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - physiology; Lymphocytes; macrophage inhibitory protein-1α; MCP; mean fluorescence intensity; Medical sciences; metabolite of leflunomide; methotrexate; Methotrexate - pharmacology; MFI; MIG; migrated; MIP-1α; monocyte chemotactic protein; MTX; NAD; NF-κB; non-adherent; nuclear factor κB; PBMC; PBS; peripheral blood mononuclear cell(s); peripheral blood mononuclear cells; Pharmacology. Drug treatments; phosphate buffered saline; rheumatoid arthritis; TEM; Transcription factors; transendothelial migration; Uridine - pharmacology
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.2003.018440

Objectives: To test whether the active metabolite of leflunomide (LEF-M), in addition to blocking the proliferation of activated lymphocytes by inhibiting dihydro-orotate dehydrogenase (DHODH), influences the transendothelial migration (TEM) of peripheral blood mononuclear cells (PBMC). Methods: In an in vitro model of PBMC transmigration through an endothelial cell (EC) barrier, PBMC were re-collected in three groups: cells not adherent to the EC, cells bound to, and cells which had migrated through, the EC layer. Experiments in which cells were pretreated with LEF-M (in the absence or in the presence of uridine) were compared with parallel experiments in the presence of medium alone. Results: Preincubation of EC with LEF-M led to a 36 (SEM 16)% reduction in PBMC TEM (p