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Ciglitazone inhibits plasmin-induced proinflammatory monocyte activation via modulation of p38 MAP kinase activity

Tatiana Syrovets1, Almut Schüle, Marina Jendrach

  • 1Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstr. 20, D-89081 Ulm, Germany.

Thrombosis and Haemostasis
|August 28, 2002
PubMed

Insights

Peroxisome proliferator-activated receptor (PPAR) gamma activation by ciglitazone inhibits plasmin-induced monocyte migration and inflammation. This finding suggests PPAR gamma agonists can control inflammatory responses at sites of tissue injury.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Plasmin induces monocyte (PM) chemotaxis and pro-inflammatory gene expression via NF-kappa B and AP-1 pathways.
  • Peripheral monocytes (PM) primarily express peroxisome proliferator-activated receptor (PPAR) gamma, with minimal PPAR alpha.
  • Macrophages and dendritic cells express different PPAR profiles compared to PM.

Purpose of the Study:

  • To investigate the role of PPAR gamma in modulating plasmin-induced monocyte responses.
  • To determine the efficacy of PPAR gamma agonists in inhibiting monocyte chemotaxis and inflammatory mediator release.
  • To elucidate the molecular mechanisms underlying PPAR gamma's anti-inflammatory effects in monocytes.

Main Methods:

  • Semiquantitative RT-PCR and immunoblotting to assess PPAR expression in PM.
  • Surface plasmon resonance to confirm ciglitazone's activation of PPAR gamma.
  • Assays for monocyte chemotaxis, cytokine release (IL-1 alpha, IL-1 beta, TNF-alpha), NF-kappa B and AP-1 activation, and p38 MAPK phosphorylation.

Main Results:

  • Ciglitazone, a PPAR gamma agonist, concentration-dependently inhibited plasmin-induced PM chemotaxis and release of IL-1 alpha, IL-1 beta, and TNF-alpha.
  • PPAR alpha agonist clofibric acid did not affect these plasmin-induced responses.
  • Ciglitazone inhibited plasmin-induced NF-kappa B and AP-1 activation and p38 MAPK phosphorylation, while not affecting LPS-induced TNF-alpha release.

Conclusions:

  • Activation of PPAR gamma by ciglitazone effectively inhibits plasmin-mediated monocyte recruitment and activation.
  • PPAR gamma represents a potential therapeutic target for controlling inflammation at sites of plasmin activity.
  • The findings highlight the specific role of PPAR gamma in regulating monocyte inflammatory responses induced by plasmin.

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