Sphingosine 1-phosphate (S1P) induces COX-2 expression and PGE2 formation via S1P receptor 2 in renal mesangial cells.
Sphingosine 1-phosphate (S1P) induces COX-2 expression and PGE2 formation via S1P receptor 2 in renal mesangial cells.
复制标题
DOI：
10.1016/j.bbalip.2013.09.009
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Anja Völzke;A. Koch;D. Meyer zu Heringdorf;A. Huwiler;J. Pfeilschifter
中科院分区：
文献类型：
--
作者：
Anja Völzke;A. Koch;D. Meyer zu Heringdorf;A. Huwiler;J. Pfeilschifter
了解1-磷酸鞘氨醇(S1P)诱导肾小球系膜细胞环氧合酶(COX)-2表达和前列腺素E_2(PGE_2)形成的机制可能为治疗炎症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促进大鼠系膜细胞COX-2表达和PGE2形成的S1P依赖的信号机制。此外，我们还研究了这些机制是否在血管紧张素II(Ang II)和促炎细胞因子IL-1β(IL-1β)存在的情况下起作用。S1P处理大鼠和人系膜细胞后，COX-2的表达呈浓度依赖性增加。药理学和分子生物学研究表明，S1P依赖的COX-2mRNA和蛋白表达增加是通过激活S1P受体2(S1P2)介导的。此外，抑制S1P2下游的Giand p42/p44 MAPK信号通路，可取消S1P诱导的COX-2表达。此外，依赖S1P/S1P2的COX-2上调导致PGE2水平显著升高，Ang II和IL-1β的存在进一步增强了这一作用。S1P/S1P信号通路下游的一个功能结果是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COX-2的迁移反应。总之，我们的结果表明，细胞外S1P通过激活S1P和随后的Giand p42/p44 MAPK依赖信号诱导肾小球系膜细胞COX-2表达，从而促进PGE2的形成和细胞迁移，这是本质上需要COX-2的途径。因此，靶向S1P/S1P信号通路可能成为治疗肾炎性疾病的新策略。
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 PGE2formation 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 Giand 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 PGE2levels, which were further potentiated in the presence of Ang II and IL-1β. A functional consequence downstream of S1P/S1P2signaling 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 S1P2and subsequent Giand p42/p44 MAPK-dependent signaling in renal mesangial cells leading to enhanced PGE2formation and cell migration that essentially requires COX-2. Thus, targeting S1P/S1P2signaling pathways might be a novel strategy to treat renal inflammatory diseases.