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

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) gamma, alpha, and retinoid X receptor alpha (RXR alpha) ligands on MCP-1-directed migrat ion and matrix metalloproteinase expression of a human acute monocytic leuk emia cell line (THP-1). PPAR gamma ligands attenuated MCP-1induced migratio n, with 50% inhibition (IC50) at 2.8 mu M for troglitazone and 4.8 mu M for rosiglitazone. PPAR alpha ligands WY-14643 (IC50: 0.9 mu M) and 5,8,11,14- eicosatetranoic acid (IC50: 9.9 mu M), and the potent RXR alpha ligand AGN 4204 (IC50: 3.6 nM) also blocked monocyte migration. Troglitazone, rosiglit azone, or AGN 4204 inhibited phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 expression. PPAR alpha 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 (TIM P-1) expression, whereas all PPAR ligands showed no effect. All PPAR and RX R alpha ligands blocked chemotaxis of THP-1 monocytes in the absence of a m atrix barrier, This study demonstrates that activated PPARs and RXR alpha, block MCP-1-directed monocyte migration, mediated, at least in part, throug h their effects on matrix metalloproteinase-9 or TIMP-1 production, or chem otaxis. (C) 2000 Elsevier Science B,V. All rights reserved.