Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes

• Published in: European journal of pharmacology 2000-08, Vol.401 (3), p.259-270
• Main Authors: Kintscher, Ulrich, Goetze, Stephan, Wakino, Shu, Kim, Sarah, Nagpal, Sunil, Chandraratna, Roshantha A.S, Graf, Kristof, Fleck, Eckart, Hsueh, Willa A, Law, Ronald E
• Format: Article
• Language: English
• Subjects: 5,8,11,14-Eicosatetraynoic Acid - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Movement - drug effects; Chemokine CCL2 - pharmacology; Chemotaxis - drug effects; Chromans - pharmacology; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Inflammation; Matrix metalloproteinase; Matrix Metalloproteinase 9 - drug effects; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Migration; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Molecular and cellular biology; Monocyte; Monocytes - cytology; Monocytes - drug effects; Peroxisome proliferator-activated receptor (PPAR); Pharmacology. Drug treatments; Pyrimidines - pharmacology; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Retinoic Acid - agonists; Retinoic Acid Receptor alpha; Retinoid X receptor (RXR); Rosiglitazone; Tetradecanoylphorbol Acetate - pharmacology; Thiazoles - pharmacology; Thiazolidinediones; Tissue Inhibitor of Metalloproteinase-1 - drug effects; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transcription Factors - agonists; Troglitazone; Tumor Cells, Cultured
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00461-1

Monocyte chemotactic protein-1 (MCP-1)-directed transendothelial migration of monocytes plays a key role in the development of inflammatory diseases. Infiltration of tissues by monocytes requires degradation of extracellular matrices, a process that involves matrix metalloproteinases. We studied the effects of peroxisome proliferator-activated receptor (PPAR) γ, α, and retinoid X receptor α (RXRα) ligands on MCP-1-directed migration and matrix metalloproteinase expression of a human acute monocytic leukemia cell line (THP-1). PPARγ ligands attenuated MCP-1-induced migration, with 50% inhibition (IC 50) at 2.8 μM for troglitazone and 4.8 μM for rosiglitazone. PPARα ligands WY-14643 (IC 50: 0.9 μM) and 5,8,11,14-eicosatetranoic acid (IC 50: 9.9 μM), and the potent RXRα ligand AGN 4204 (IC 50: 3.6 nM) also blocked monocyte migration. Troglitazone, rosiglitazone, or AGN 4204 inhibited phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 expression. PPARα activators WY-14643 and 5,8,11,14-eicosatetraynoic acid, however, had no inhibitory effect. AGN 4204 increased PMA-induced tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) expression, whereas all PPAR ligands showed no effect. All PPAR and RXRα ligands blocked chemotaxis of THP-1 monocytes in the absence of a matrix barrier. This study demonstrates that activated PPARs and RXRα, block MCP-1-directed monocyte migration, mediated, at least in part, through their effects on matrix metalloproteinase-9 or TIMP-1 production, or chemotaxis.