Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE(2) in an in vitro equine inflammation model.
Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE(2) in an in vitro equine inflammation model.
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DOI：
10.1016/j.vetimm.2017.09.008
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发表时间：
2017-10
影响因子：
1.8
通讯作者：
Jones SL
中科院分区：
文献类型：
--
作者：
Martin EM;Jones SL
抑制前列腺素 E2 (PGE2) 的产生可有效限制马的炎症，但通过环加氧酶 (COX) 抑制的非特异性前列腺素阻断会在马患者中引起有害的胃肠道副作用。因此，需要更具选择性的 PGE2 靶向疗法来治疗马的炎症性疾病。一个潜在的靶点是微粒体前列腺素 E-合酶-1 (mPGES-1)，它是诱导型 PGE2 合成级联中 COX-2 下游的终端酶。这种酶尚未在马白细胞中进行研究，马白细胞在马炎症性疾病中发挥着关键作用。本研究的目的是确定 mPGES-1 是否是马白细胞中 PGE2 选择性抗炎靶标。为了评估这一目标，从六匹混合品种和性别的健康成年马的颈静脉穿刺收集的马全血中分离出富含白细胞的血浆（LRP）。 LRP 用粒细胞-单核细胞集落刺激因子 (GM-CSF) 引发，并在存在或不存在 mPGES-1 抑制剂 (MF63)、COX-2 抑制剂 (NS-398) 或非选择性 COX 抑制剂（吲哚美辛）的情况下用脂多糖 (LPS) 刺激。治疗后，分别通过 qPCR 和蛋白质印迹测量 mPGES-1 和 COX-2 mRNA 和蛋白质水平，并通过 ELISA 测量细胞上清液中 PGE2、血栓素 (TXA2) 和前列环素 (PGI2) 水平。这项研究表明，分别通过 qPCR 和蛋白质印迹测量，LPS 显着增加了马 LRP 中 mPGES-1 mRNA 的水平，但没有增加蛋白质水平。相反，LPS 协同诱导 COX-2 mRNA 和蛋白。重要的是，用吲哚美辛和 NS-398 处理 LPS 刺激的白细胞可显着降低多种前列腺素类药物（PGE2、TXA2 和 PGI2）的细胞外浓度，而 mPGES-1 抑制剂 MF63 仅选择性抑制 PGE2 的产生。与任一 COX 抑制剂相比，mPGES-1 抑制还保留了较高的 PGE2 产生基础水平，这在临床环境中可能是有益的。总之，这项工作将 mPGES-1 确定为 PGE2 产生的关键调节因子和马白细胞中的 PGE2 选择性靶标。这项研究表明，与传统的非甾体抗炎药相比，mPGES-1 是治疗马炎症性疾病的潜在更安全、有效的治疗靶点。
Inhibition of prostaglandin E2 (PGE2) production effectively limits inflammation in horses, however nonspecific prostaglandin blockade via cyclooxygenase (COX) inhibition elicits deleterious gastrointestinal side effects in equine patients. Thus, more selective PGE2 targeting therapeutics are needed to treat inflammatory disease in horses. One potential target is microsomal prostaglandin E-synthase-1 (mPGES-1), which is the terminal enzyme downstream of COX-2 in the inducible PGE2 synthesis cascade. This enzyme has yet to be studied in equine leukocytes, which play a pivotal role in equine inflammatory disease. The objective of this study was to determine if mPGES-1 is a PGE2-selective anti-inflammatory target in equine leukocytes. To evaluate this objective, leukocyte-rich plasma (LRP) was isolated from equine whole blood collected via jugular venipuncture of six healthy adult horses of mixed breeds and genders. LRP was primed with granulocyte-monocyte colony-stimulating factor (GM-CSF) and stimulated with lipopolysaccharide (LPS) in the presence or absence of an mPGES-1 inhibitor (MF63), a COX-2 inhibitor (NS-398), or a nonselective COX inhibitor (indomethacin). Following treatment, mPGES-1 and COX-2 mRNA and protein levels were measured via qPCR and western blot, respectively, and PGE2, thromboxane (TXA2) and prostacyclin (PGI2) levels were measured in cellular supernatants via ELISA. This study revealed that LPS significantly increased mPGES-1 mRNA, but not protein levels in equine LRP as measured by qPCR and western blot, respectively. In contrast, COX-2 mRNA and protein were coordinately induced by LPS. Importantly, treatment of LPS-stimulated leukocytes with indomethacin and NS-398 significantly reduced extracellular concentrations of multiple prostanoids (PGE2, TXA2 and PGI2), while the mPGES-1 inhibitor MF63 selectively inhibited PGE2 production only. mPGES-1 inhibition also preserved higher basal levels of PGE2 production when compared to either COX inhibitor, which might be beneficial in a clinical setting. In conclusion, this work identifies mPGES-1 as a key regulator of PGE2 production and a PGE2-selective target in equine leukocytes. This study demonstrates that mPGES-1 is a potentially safer and effective therapeutic target for treatment of equine inflammatory disease when compared to traditional non-steroidal anti-inflammatory drugs.
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影响因子：
4.8
作者：
Murakami, M;Naraba, H;Kudo, I
通讯作者：
Kudo, I
DOI：
10.1016/j.bbalip.2007.06.002
发表时间：
2007-09-01
影响因子：
4.8
作者：
St-Onge, Mireille;Flamand, Nicolas;Pouliot, Marc
通讯作者：
Pouliot, Marc
影响因子：
1.8
作者：
Eckert, Rachael E.;Neuder, Laura E.;Jones, Samuel L.
通讯作者：
Jones, Samuel L.
影响因子：
1
作者：
Brideau, C;Van Staden, C;Chan, CC
通讯作者：
Chan, CC
影响因子：
--
作者：
Sharma JN;Jawad NM
通讯作者：
Jawad NM