Völzke Anja, Koch Alexander, Meyer Zu Heringdorf Dagmar, Huwiler Andrea, Pfeilschifter Josef
Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Biochim Biophys Acta. 2014 Jan;1841(1):11-21. doi: 10.1016/j.bbalip.2013.09.009. Epub 2013 Sep 21.
Understanding the mechanisms of sphingosine 1-phosphate (S1P)-induced cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) formation in renal mesangial cells may provide potential therapeutic targets to treat inflammatory glomerular diseases. Thus, we evaluated the S1P-dependent signaling mechanisms which are responsible for enhanced COX-2 expression and PGE2 formation in rat mesangial cells under basal conditions. Furthermore, we investigated whether these mechanisms are operative in the presence of angiotensin II (Ang II) and of the pro-inflammatory cytokine interleukin-1β (IL-1β). Treatment of rat and human mesangial cells with S1P led to concentration-dependent enhanced expression of COX-2. Pharmacological and molecular biology approaches revealed that the S1P-dependent increase of COX-2 mRNA and protein expression was mediated via activation of S1P receptor 2 (S1P2). Further, inhibition of Gi and p42/p44 MAPK signaling, both downstream of S1P2, abolished the S1P-induced COX-2 expression. In addition, S1P/S1P2-dependent upregulation of COX-2 led to significantly elevated PGE2 levels, which were further potentiated in the presence of Ang II and IL-1β. A functional consequence downstream of S1P/S1P2 signaling is mesangial cell migration that is stimulated by S1P. Interestingly, inhibition of COX-2 by celecoxib and SC-236 completely abolished the migratory response. Overall, our results demonstrate that extracellular S1P induces COX-2 expression via activation of S1P2 and subsequent Gi and p42/p44 MAPK-dependent signaling in renal mesangial cells leading to enhanced PGE2 formation and cell migration that essentially requires COX-2. Thus, targeting S1P/S1P2 signaling pathways might be a novel strategy to treat renal inflammatory diseases.
了解1-磷酸鞘氨醇（S1P）诱导肾系膜细胞中环氧合酶（COX）-2表达和前列腺素E2（PGE2）生成的机制，可能为治疗炎性肾小球疾病提供潜在的治疗靶点。因此，我们评估了在基础条件下，负责大鼠系膜细胞中COX-2表达增强和PGE2生成的S1P依赖性信号传导机制。此外，我们研究了在存在血管紧张素II（Ang II）和促炎细胞因子白细胞介素-1β（IL-1β）的情况下，这些机制是否起作用。用S1P处理大鼠和人系膜细胞导致COX-2表达呈浓度依赖性增强。药理学和分子生物学方法表明，S1P依赖性COX-2 mRNA和蛋白表达的增加是通过激活S1P受体2（S1P2）介导的。此外，抑制S1P2下游的Gi和p42/p44 MAPK信号传导，消除了S1P诱导的COX-2表达。此外，S1P/S1P2依赖性COX-2上调导致PGE2水平显著升高，在存在Ang II和IL-1β的情况下进一步增强。S1P/S1P2信号传导下游的一个功能后果是S1P刺激的系膜细胞迁移。有趣的是，塞来昔布和SC-236对COX-2的抑制完全消除了迁移反应。总体而言，我们的结果表明，细胞外S1P通过激活S1P2以及随后肾系膜细胞中Gi和p42/p44 MAPK依赖性信号传导诱导COX-2表达，导致PGE2生成增加和细胞迁移，而这基本上需要COX-2。因此，靶向S1P/S1P2信号通路可能是治疗肾脏炎症性疾病的一种新策略。
