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

Eur J Pharmacol. 2000 Aug 11;401(3):259-70. 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) gamma, alpha, and retinoid X receptor alpha (RXRalpha) ligands on MCP-1-directed migration and matrix metalloproteinase expression of a human acute monocytic leukemia cell line (THP-1). PPARgamma ligands attenuated MCP-1-induced migration, with 50% inhibition (IC(50)) at 2.8 microM for troglitazone and 4.8 microM for rosiglitazone. PPARalpha ligands WY-14643 (IC(50): 0.9 microM) and 5,8,11,14-eicosatetranoic acid (IC(50): 9.9 microM), and the potent RXRalpha 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. PPARalpha 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 RXRalpha ligands blocked chemotaxis of THP-1 monocytes in the absence of a matrix barrier. This study demonstrates that activated PPARs and RXRalpha, block MCP-1-directed monocyte migration, mediated, at least in part, through their effects on matrix metalloproteinase-9 or TIMP-1 production, or chemotaxis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5,8,11,14-Eicosatetraynoic Acid / pharmacology
  • 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
  • Humans
  • Matrix Metalloproteinase 9 / drug effects
  • Matrix Metalloproteinase 9 / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Monocytes / cytology
  • Monocytes / drug effects*
  • Pyrimidines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Retinoic Acid / agonists*
  • Retinoic Acid Receptor alpha
  • 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


  • Chemokine CCL2
  • Chromans
  • Enzyme Inhibitors
  • Flavonoids
  • Pyrimidines
  • RARA protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Thiazoles
  • Thiazolidinediones
  • Tissue Inhibitor of Metalloproteinase-1
  • Transcription Factors
  • Rosiglitazone
  • 5,8,11,14-Eicosatetraynoic Acid
  • pirinixic acid
  • Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 9
  • Troglitazone
  • Tetradecanoylphorbol Acetate
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one