Cytosolic phospholipase a, is required for macrophage arachidonic acid release by agonists that do and do not mobilize calcium - Novel role of mitogen-activated protein kinase pathways in cytosolic phospholipase A(2) regulation

The 85-kDa cytosolic phospholipase A(2) (cPLA(2)) mediates agonist-induced arachidonic acid release and eicosanoid production. Calcium and phosphoryla tion on Ser-505 by mitogen-activated protein kinases (MAPKs) regulate cPLA( 2). Arachidonic acid release and eicosanoid production induced by stimuli t hat do (A23187, zymosan) or do not (phorbol myristate acetate (PMA), okadai c acid) mobilize calcium were quantitatively suppressed in cPLA(2)-deficien t mouse peritoneal macrophages. The contribution of MAPKs to cPLA(2)-mediat ed arachidonic acid release was investigated. Both extracellular signal-reg ulated kinases (ERKs) and p38 contributed to cPLA(2) phosphorylation on Ser -505. However, although ERK inhibition did not affect A23187-induced arachi donic acid release, it suppressed zymosan-, PMA-, and okadaic acid-induced arachidonic acid release under conditions where phosphorylation of cPLA(2) on Ser-505 was unaffected. This indicates an additional regulatory mechanis m for the ERK pathway. A role for transcriptional regulation is suggested b y data showing that cycloheximide and actinomycin D inhibited arachidonic a cid release induced by zymosan, PMA and, okadaic acid but not by A23181, Ou r results show that MAPK pathways contribute to arachidonic acid release in macrophages through alternative mechanisms in addition to their ability to phosphorylate cPLA(2) on Ser-505 and suggest a role for new protein synthe sis.