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

• Published in: Thrombosis and haemostasis Vol. 88; no. 2; p. 274
• Main Authors: Syrovets, Tatiana, Schüle, Almut, Jendrach, Marina, Büchele, Berthold, Simmet, Thomas
• Format: Journal Article
• Language: English
• Published: Germany 01.08.2002
• Subjects: Chemotaxis, Leukocyte - drug effects; Fibrinolysin - antagonists & inhibitors; Fibrinolysin - physiology; Humans; Inflammation - pathology; Interleukin-1 - secretion; Mitogen-Activated Protein Kinases - drug effects; Mitogen-Activated Protein Kinases - metabolism; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; p38 Mitogen-Activated Protein Kinases; Phosphorylation - drug effects; Receptors, Cytoplasmic and Nuclear - agonists; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factors - agonists; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - secretion
• DOI: 10.1055/s-0037-1613198
• ISSN: 0340-6245

Plasmin triggers chemotaxis and NF-kappa B- and AP-1-mediated proinflammatory gene expression in human peripheral monocytes (PM). Compared with macrophages and dendritic cells, PM express mainly the peroxisome proliferator-activated receptor (PPAR) gamma and traces of PPAR alpha as detected by semiquantitative RT-PCR and immunoblotting. The PPAR gamma agonist ciglitazone, but not the PPAR alpha agonist clofibric acid, concentration-dependently inhibited the plasmin-, but not the FMLP-induced PM chemotaxis. Similarly, release of interleukin (IL)-1 alpha, IL-1 beta and tumor necrosis factor (TNF)-alpha from plasmin-stimulated PM was concentration-dependently inhibited by ciglitazone, but not by clofibric acid, while the LPS-induced TNF-alpha release remained unaffected by any of both PPAR agonists. Ciglitazone activates PPAR gamma as shown by a novel surface plasmon resonance analysis and inhibits the plasmin-induced activation of NF-kappa B and AP-1. It also inhibits p38 MAPK phosphorylation essential for the plasmin-induced PM chemotaxis and gene activation. Thus, activation of PPAR gamma by ciglitazone may allow controLling of the plasmin-mediated recruitment and activation of PM at sites of inflammation.