Murray Joanna, Ward Carol, O'Flaherty Joseph T, Dransfield Ian, Haslett Christopher, Chilvers Edwin R, Rossi Adriano G
Rayne Laboratory, Respiratory Medicine Unit, Centre for Inflammation Research, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG.
Br J Pharmacol. 2003 May;139(2):388-98. doi: 10.1038/sj.bjp.0705265.
1 Since most inflammatory mediators that stimulate granulocyte responsiveness also delay apoptosis, it is often assumed that activation and longevity are causally related. Using isolated human peripheral blood neutrophils and eosinophils, we examined this association by exploiting the proinflammatory lipid mediators, the leukotrienes (LTs), and investigated granulocyte function and apoptosis. 2 LTB(4) induced elevation of intracellular free Ca(2+) concentration (Ca(2+)), cell polarisation and retardation of neutrophil apoptosis, although the antiapoptotic effect occurred only at concentrations > or =300 nM. LTB(4)-induced activation was attenuated by CP-105,696, a BLT1-specific antagonist suggesting classical LTB(4) receptor BLT1 involvement. 3 Despite demonstrating the presence of the neutrophil intracellular LTB(4) receptor peroxisome-proliferator activator receptor-alpha (PPARalpha) in neutrophils, the selective PPARalpha agonist WY-14,643 did not mimic LTB(4)-induced prosurvival effects. 4 LTB(4)-induced survival, however, also appeared to be mediated by BLT1 since CP-105,696 inhibited the LTB(4)-mediated antiapoptotic effect. Furthermore, based on studies with CP-105,696 and 5-lipoxygenase inhibitors, lipopolysaccharide (LPS)-, granulocyte-macrophage colony-stimulating factor (GM-CSF)-, dexamethasone- and dibutyryl-cAMP (db-cAMP)-induced delay of neutrophil apoptosis did not involve autocrine production of LTB(4). 5 Although LTB(4) and LTD(4) induced human eosinophil Ca(2+) elevation and polarization, these LTs did not influence eosinophil apoptosis. Furthermore, LTB(4)- and LTD(4)-induced eosinophil activation was attenuated by CP-105,696 and the Cys-LT(1) receptor antagonist montelukast, respectively, highlighting specific receptor dependency. 6 Thus, mediator-triggered granulocyte activation and antiapoptotic pathways are distinct events that can be differentially regulated.
1 由于大多数刺激粒细胞反应性的炎症介质也会延迟细胞凋亡，因此人们常常认为激活和寿命存在因果关系。我们使用分离的人外周血中性粒细胞和嗜酸性粒细胞，通过利用促炎脂质介质白三烯（LTs）来研究这种关联，并研究粒细胞功能和细胞凋亡。2 白三烯B4（LTB4）可诱导细胞内游离钙浓度（[Ca2+]i）升高、细胞极化以及中性粒细胞凋亡延迟，不过抗凋亡作用仅在浓度≥300 nM时出现。CP-105,696（一种BLT1特异性拮抗剂）可减弱LTB4诱导的激活作用，提示经典的LTB4受体BLT1参与其中。3 尽管已证实在中性粒细胞中存在中性粒细胞细胞内LTB4受体过氧化物酶体增殖物激活受体α（PPARα），但选择性PPARα激动剂WY-14,643并不能模拟LTB4诱导的促存活效应。4 然而，LTB4诱导的存活似乎也由BLT1介导，因为CP-105,696可抑制LTB4介导的抗凋亡作用。此外，基于对CP-105,696和5-脂氧合酶抑制剂的研究，脂多糖（LPS）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、地塞米松和二丁酰环磷腺苷（db-cAMP）诱导的中性粒细胞凋亡延迟并不涉及LTB4的自分泌产生。5 尽管LTB4和白三烯D4（LTD4）可诱导人嗜酸性粒细胞[Ca2+]i升高和极化，但这些LTs并不影响嗜酸性粒细胞凋亡。此外，CP-105,696和半胱氨酰白三烯1（Cys-LT1）受体拮抗剂孟鲁司特分别减弱了LTB4和LTD4诱导的嗜酸性粒细胞激活，突出了特定的受体依赖性。6 因此，介质触发的粒细胞激活和抗凋亡途径是不同的事件，可受到不同的调节。
