Concomitant Recruitment of ERK1/2 and p38 MAPK Signalling Pathway Is Required for Activation of Cytoplasmic Phospholipase A2via ATP in Articular Chondrocytes

• Published in: The Journal of biological chemistry 2003-04, Vol.278 (16), p.13680-13687
• Main Authors: Berenbaum, Francis, Humbert, Lydie, Bereziat, Gilbert, Thirion, Sylvie
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M211570200

Extracellular ATP is a pro-inflammatory mediator involved in the release of prostaglandin from articular chondrocytes, but little is known about its effects on intracellular signaling. ATP triggered the rapid release of prostaglandin E2(PGE2) by acting on P2Y2 receptors in rabbit articular chondrocytes. We have explored the signaling events involved in this synthesis. ATP significantly increased arachidonic acid production, which involved the activation of the 85-kDa cytosolic phospholipase A2 (cPLA2) but not a secreted form of PLA2, as demonstrated by various PLA2 inhibitors and translocation experiments. We also showed that ATP induced the phosphorylation of p38 and ERK1/2 mitogen-activated-protein kinases (MAPKs). Both PD98059, an inhibitor of the ERK pathway, and SB203580, an inhibitor of p38 MAPK, completely inhibited the ATP-induced release of PGE2. Finally, dominant-negative plasmids encoding p38 and ERK transfected alone into the cells impaired the ATP-induced release of PGE2 to about the same extent as both plasmids transfected together. These results suggest that PGE2 production induced by ATP requires the activation of both ERK1/2 and p38 MAPKs. Thus, ATP acts via P2Y2-purine receptors to recruit cPLA2 by activating both ERK1/2 and p38 MAPKs and stimulates the release of PGE2 from articular chondrocytes.