The PGE2-induced inhibition of the PLD activation pathway stimulated by fMLP in human neutrophils is mediated by PKA at the PD-Kγ level
The PGE2-induced inhibition of the PLD activation pathway stimulated by fMLP in human neutrophils is mediated by PKA at the PD-Kγ level
复制标题
DOI：
10.1016/j.bcp.2007.06.013
复制
发表时间：
2007-09-01
影响因子：
5.8
通讯作者：
Bourgoin, Sylvain G.
中科院分区：
文献类型：
--
作者：
Burelout, Chantal;Thibault, Nathalie;Bourgoin, Sylvain G.
前列腺素E-2（PGE（2））是一种调节炎症的类花生酸，可抑制中性粒细胞中几种趋化因子诱导的功能，如趋化性、超氧阴离子的产生、粘附、细胞毒性酶的分泌和白三烯B-4的合成。我们先前报道PGE（2）通过抑制P13-K γ活性和减少PLD激活因子PKC、Rho和Arf-GTP酶向膜的募集来抑制导致PLD激活的fMLP信号通路。PGE（2）通过EP 2受体对fMLP诱导的大多数功能反应的抑制作用是由PKA介导的，但趋化反应除外。我们已经研究了PKA在EP 2介导的PLD激活途径抑制中的作用。H-89是一种选择性PKA药理学抑制剂，它能抑制PGE（2）在fMLP激活的PLD通路的所有阶段的抑制作用，即PLD活性、PKC α、Rho和Arf-GTP酶的膜转位、钙离子内流、蛋白质的酪氨酸磷酸化和最终PI 3-K的p110 γ催化亚基的膜转位。然而，PLD和PI 3-K γ都不是PKA的底物。这些数据提供的证据表明，PGE（2）刺激的PKA活性在PI 3-K γ水平调节fMLP刺激的PLD通路，PKA抑制PI 3-K γ活化是一个复杂的机制，仍有待完全阐明。(C)2007年爱思唯尔公司All rights reserved.
Prostaglandin E-2 (PGE(2)), an eicosanoid that modulates inflammation, inhibits several chemoattractant-elicited functions in neutrophils such as chemotaxis, production of superoxide anions, adhesion, secretion of cytotoxic enzymes and synthesis of leukotriene B-4. We previously reported that PGE(2) inhibits the fMLP signaling pathway that leads to PLD activation through suppression of P13-K gamma activity and the decreased recruitment to membranes of PLD activation factors, PKC, Rho and Arf-GTPases. This effect is mediated via the EP2 receptors known to raise cAMP in cells.The inhibition of most fMLP-induced functional responses by PGE(2) via EP2 receptors is mediated by PKA, except the chernotactic response. We have investigated the role of PKA in the EP2-mediated inhibition of the PLD activation pathway. H-89, a selective PKA pharmacological inhibitor suppressed the inhibitory effects of PGE(2) at all stages of the PLD pathway activated by fMLP, i.e. PLD activity, translocation to membranes of PKC alpha, Rho and Arf-GTPases, calcium influx, tyrosine phosphorylation of proteins and finally translocation of p110 gamma catalytic subunit of PI3-K to membranes. However, neither PLD nor PI3-K gamma was substrate of PKA. These data provide evidence that PGE(2)-stimulated PKA activity regulates the PLD pathway stimulated by fMLP at the level of PI3-K gamma and that the inhibition of PI3-K gamma activation by PKA is a complex mechanism that remains to be completely elucidated. (C) 2007 Elsevier Inc. All rights reserved.