Activation of Arachidonate Release and Cytosolic Phospholipase A2 via Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase in Macrophages Stimulated by Bacteria or Zymosan

The mitogen-activated protein kinases (MAP kinases), extracellular signal-regulated kinase (ERK) and p38, can both contribute to the activation of cytosolic phospholipase A₂ (cPLA₂). We have investigated the hypothesis that ERK and p38 together or independent of one another play roles in the regulation of cPLA₂ in macrophages responding to the oral bacterium Prevotella intermedia or zymosan. Stimulation with bacteria or zymosan beads caused arachidonate release and enhanced in vitro cPLA₂ activity of cell lysate by 1.5- and 1.7-fold, respectively, as well as activation of ERK and p38. The specific inhibitor of MAP kinase kinase, PD 98059, and the inhibitor of p38, SB 203580, both partially inhibited cPLA₂ activation and arachidonate release induced by bacteria and zymosan. Together, the two inhibitors had additive effects and completely blocked cPLA₂ activation and arachidonate release. The present results demonstrate that ERK and p38 both have important roles in the regulation of cPLA₂ and together account for its activation in P. intermedia and zymosan-stimulated mouse macrophages.