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 A2 regulation
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 A2 regulation
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DOI：
10.1074/jbc.m908941199
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发表时间：
2000-06-30
影响因子：
4.8
通讯作者：
Leslie, CC
中科院分区：
文献类型：
--
作者：
Gijón, MA;Spencer, DM;Leslie, CC
85-kDa胞质磷脂酶A（2）（cPLA（2））介导激动剂诱导的花生四烯酸释放和类花生酸产生。钙离子和丝裂原活化蛋白激酶（MAPK）对Ser-505的磷酸化调节cPLA（2）。在cPLA（2）缺陷小鼠腹腔巨噬细胞中，由能够（A23187，酵母聚糖）或不能够（佛波醇肉豆蔻酸乙酸酯（PMA），冈田酸）动员钙的刺激诱导的花生四烯酸释放和类花生酸产生被定量抑制。研究了MAPKs对cPLA（2）介导的花生四烯酸释放的贡献。细胞外信号调节激酶（ERK）和p38都有助于cPLA（2）在Ser-505上的磷酸化。然而，尽管ERK抑制不影响A23187诱导的花生四烯酸释放，但在cPLA（2）在Ser-505上的磷酸化不受影响的条件下，ERK抑制酵母聚糖、PMA和冈田酸诱导的花生四烯酸释放。这表明ERK途径的另外的调节机制。放线菌酮和放线菌素D抑制酵母聚糖、PMA和冈田酸诱导的花生四烯酸释放，但不抑制A23181诱导的花生四烯酸释放，这表明放线菌酮和放线菌素D在转录调控中发挥作用。我们的结果表明，MAPK途径除了能够磷酸化Ser-505上的cPLA（2）外，还通过其他机制促进巨噬细胞中花生四烯酸的释放，并表明其在新蛋白质合成中的作用。
The 85-kDa cytosolic phospholipase A(2) (cPLA(2)) mediates agonist-induced arachidonic acid release and eicosanoid production. Calcium and phosphorylation on Ser-505 by mitogen-activated protein kinases (MAPKs) regulate cPLA(2). Arachidonic acid release and eicosanoid production induced by stimuli that do (A23187, zymosan) or do not (phorbol myristate acetate (PMA), okadaic acid) mobilize calcium were quantitatively suppressed in cPLA(2)-deficient mouse peritoneal macrophages. The contribution of MAPKs to cPLA(2)-mediated arachidonic acid release was investigated. Both extracellular signal-regulated kinases (ERKs) and p38 contributed to cPLA(2) phosphorylation on Ser-505. However, although ERK inhibition did not affect A23187-induced arachidonic 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 mechanism for the ERK pathway. A role for transcriptional regulation is suggested by data showing that cycloheximide and actinomycin D inhibited arachidonic acid release induced by zymosan, PMA and, okadaic acid but not by A23181, Our 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 synthesis.