Ciglitazone inhibits plasmin-induced proinflammatory monocyte activation via modulation of p38 MAP kinase activity.
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.
Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstr. 20, D-89081 Ulm, Germany.
Tatiana
T
Syrovets
Almut
A
Schüle
Marina
M
Jendrach
Berthold
B
Büchele
Thomas
T
Simmet
D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005341:Fibrinolysin; C039671:ciglitazone