Stankova Jana, Turcotte Sylvie, Harris Jennifer, Rola-Pleszczynski Marek
Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
J Immunol. 2002 Apr 1;168(7):3570-6. doi: 10.4049/jimmunol.168.7.3570.
Glucocorticoids can down-regulate many inflammatory and immune responses and constitute a powerful therapeutic tool in a number of diseases. However, they have a somewhat paradoxical effect on neutrophils, in that they prolong their survival. Because leukotriene B(4) (LTB(4)) can also extend neutrophil survival, we proposed that glucocorticoids could prevent neutrophil apoptosis by up-regulating their expression of the high-affinity LTB(4) receptor (BLT1). Here we show that, indeed, dexamethasone (DEX) up-regulates the steady-state levels of BLT1 mRNA in human neutrophils. The effect was time and concentration dependent, being maximal at 4 h and at 10-100 nM DEX. The effect was also dependent on transcriptional activity, whereas BLT1 mRNA stability was not affected. DEX-induced up-regulation of BLT1 expression was prevented by pretreatment with the LTB(4) antagonist LY255283. Moreover, LTB(4) itself up-regulated the expression of BLT1 mRNA. BLT1 protein expression on neutrophils exposed to DEX for 24 h was also up-regulated 2- to 3-fold, and DEX-treated as well as LTB(4)-treated cells showed enhanced responsiveness to LTB(4) in terms of intracellular Ca(2+) mobilization and chemotaxis. Whereas DEX and LTB(4) alone decreased neutrophil apoptosis by approximately 50%, neutrophils treated with both LTB(4) and DEX showed >90% survival at 24 h. Moreover, BLT1 antagonists prevented the increased neutrophil survival induced by DEX as well as by LTB(4). Taken together, our results suggest that DEX-induced up-regulation of BLT1 expression in neutrophils may be one mechanism through which glucocorticoids can prolong neutrophil survival, namely by enhancing cell responses to the antiapoptotic effect of LTB(4).
糖皮质激素可下调多种炎症和免疫反应，是多种疾病强有力的治疗手段。然而，它们对中性粒细胞有某种矛盾的作用，即延长其存活时间。由于白三烯B4（LTB4）也能延长中性粒细胞存活时间，我们推测糖皮质激素可通过上调高亲和力LTB4受体（BLT1）的表达来防止中性粒细胞凋亡。在此我们表明，事实上，地塞米松（DEX）上调人中性粒细胞中BLT1 mRNA的稳态水平。该效应具有时间和浓度依赖性，在4小时以及10 - 100 nM DEX时达到最大值。该效应还依赖于转录活性，而BLT1 mRNA稳定性不受影响。用LTB4拮抗剂LY255283预处理可阻止DEX诱导的BLT1表达上调。此外，LTB4本身上调BLT1 mRNA的表达。暴露于DEX 24小时的中性粒细胞上BLT1蛋白表达也上调了2至3倍，并且DEX处理以及LTB4处理的细胞在细胞内Ca2 +动员和趋化性方面对LTB4的反应性增强。单独的DEX和LTB4可使中性粒细胞凋亡减少约50%，而同时用LTB4和DEX处理的中性粒细胞在24小时时存活率>90%。此外，BLT1拮抗剂可阻止DEX以及LTB4诱导的中性粒细胞存活增加。综上所述，我们的结果表明，DEX诱导中性粒细胞中BLT1表达上调可能是糖皮质激素延长中性粒细胞存活时间的一种机制，即通过增强细胞对LTB4抗凋亡作用的反应。
