The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland.
The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland; Coxa Hospital for Joint Replacement, Tampere, Finland.
Int Immunopharmacol. 2019 Jun;71:139-143. doi: 10.1016/j.intimp.2019.03.014. Epub 2019 Mar 18.
Microsomal prostaglandin E synthase-1 (mPGES-1) catalyses the formation of PGE in inflammatory tissues. It is considered a potential drug target in inflammatory conditions to achieve clinical benefits comparable to NSAIDs with a better tolerability. Inhibitors of mPGES-1 are under development but the pharmacological regulation of mPGES-1 expression remains poorly known. MAP kinase phosphatase-1 (MKP-1) is an enzyme that limits the activity of pro-inflammatory MAP kinases p38 and JNK. In the present study, we discovered that dexamethasone down-regulates mPGES-1 expression in articular chondrocytes in an MKP-1 and p38 kinase dependent manner.
Primary human chondrocytes were isolated from cartilage samples obtained from osteoarthritis (OA) patients undergoing knee replacement surgery. Primary mouse chondrocytes were isolated from cartilage samples of MKP-1 deficient (knock-out, KO) and corresponding wild type (WT) mice. Expression of mPGES-1 and MKP-1 were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot, and MAP kinase phosphorylation by Western blot.
Dexamethasone inhibited the expression of mPGES-1 in primary human chondrocytes and in chondrocytes from wild type but not from MKP-1 deficient mice. Dexamethasone enhanced MKP-1 expression in chondrocytes from wild type mice as well as in primary human OA chondrocytes. Dexamethasone induced the dephosphorylation of both p38 and JNK, whereas mPGES-1 expression was downregulated by selective inhibitors of p38 only.
The results show that MKP-1 is a crucial mediator of pharmacological control of inflammatory mPGES-1 expression by glucocorticoids, and underline MKP-1 as a potential anti-inflammatory drug target.
微粒体前列腺素 E 合酶-1（mPGES-1）在炎症组织中催化 PGE 的形成。它被认为是炎症情况下的潜在药物靶点，以实现与 NSAIDs 相当的临床益处，同时具有更好的耐受性。mPGES-1 的抑制剂正在开发中，但 mPGES-1 表达的药理学调节仍知之甚少。丝裂原活化蛋白激酶磷酸酶-1（MKP-1）是一种限制促炎 MAP 激酶 p38 和 JNK 活性的酶。在本研究中，我们发现地塞米松以 MKP-1 和 p38 激酶依赖的方式下调关节软骨细胞中的 mPGES-1 表达。
从接受膝关节置换手术的骨关节炎（OA）患者的软骨样本中分离原代人软骨细胞。从小鼠软骨样本中分离 MKP-1 缺失（敲除，KO）和相应野生型（WT）的原代鼠软骨细胞。通过定量逆转录聚合酶链反应（qRT-PCR）和 Western blot 测量 mPGES-1 和 MKP-1 的表达，通过 Western blot 测量 MAP 激酶磷酸化。
地塞米松抑制原代人软骨细胞和野生型软骨细胞中 mPGES-1 的表达，但不能抑制 MKP-1 缺失的软骨细胞中 mPGES-1 的表达。地塞米松增强了野生型小鼠软骨细胞和原代人 OA 软骨细胞中的 MKP-1 表达。地塞米松诱导 p38 和 JNK 的去磷酸化，而 mPGES-1 的表达仅被 p38 的选择性抑制剂下调。
结果表明，MKP-1 是糖皮质激素对炎症性 mPGES-1 表达进行药理学控制的关键介质，并强调 MKP-1 作为潜在的抗炎药物靶点。
