Activation of PAF receptor by oxidised LDL in human monocytes stimulates chemokine releases but not urokinase-type plasminogen activator expression.
BACKGROUND
We investigated whether the increase of urokinase-type plasminogen activator (uPA) monocyte expression and chemokine releases induced by oxidised low density lipoproteins (LDL), which participate to vascular tissue remodeling and to atherosclerotic plaque rupture, involved proinflammatory phospholipid products having platelet-activating factor (PAF)-like activity via the PAF-receptor pathway.


METHODS
uPA monocyte expression was stimulated by either copper ions-oxidised or O2*-/HO* free radical-oxidised LDL. The effects of PAF and oxidised LDL on the production of monocyte chemoattractant protein-1 and interleukin-8 were also examined.


RESULTS
Synthetic PAF significantly enhanced chemokine releases (P<0.001) without modifying uPA expression. Copper-oxidised LDL, which exhibit a higher content in lysophosphatidylcholines than free radical-oxidised LDL, induced a significantly higher enhancement in uPA expression (P<0.05). By contrast, free radical-oxidised LDL were more efficient than copper-oxidised LDL to increase chemokine releases (P<0.01). Oxidised LDL-enhanced uPA expressions were not altered by the PAF-receptor antagonist SR27417, whereas increases in chemokine releases induced by oxidised LDL and by PAF were abolished. PAF-acetylhydrolase activity was rapidly and largely inhibited in free radical-oxidised LDL when compared to copper-oxidised LDL, suggesting that free radical-oxidised LDL would contain a higher content in PAF-like products than copper-oxidised LDL.


CONCLUSIONS
Our results indicated that PAF-like oxidation products are responsible for the monocyte chemokine releases, but did not contribute to the enhanced monocyte uPA expression by oxidised LDL.
Beaudeux
Jean-Louis
JL
Laboratoire de Biochimie, EA 3617, Faculté des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, 75006 Paris, France. jean-louis.beaudeux@univ-paris5.fr
Said
Toihiri
T
Ninio
Ewa
E
Ganné
Florence
F
Soria
Jeannette
J
Delattre
Jacques
J
Soria
Claudine
C
Legrand
A
A
Peynet
Jacqueline
J
D002478:Cells, Cultured; D054407:Chemokine CCL4; D018925:Chemokines / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D009000:Monocytes / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D054407:Chemokine CCL4; D018925:Chemokines; D005609:Free Radicals; D016209:Interleukin-8; D008077:Lipoproteins, LDL; D019402:Macrophage Inflammatory Proteins; D010743:Phospholipids; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C099252:oxidized low density lipoprotein; C039351:platelet activating factor receptor; D003300:Copper; D014568:Urokinase-Type Plasminogen Activator