Dexmedetomidine inhibits LPS-induced inflammatory responses through peroxisome proliferator-activated receptor gamma (PPARγ) activation following binding to α2 adrenoceptors
Dexmedetomidine inhibits LPS-induced inflammatory responses through peroxisome proliferator-activated receptor gamma (PPARγ) activation following binding to α2 adrenoceptors
复制标题
右美托咪定通过与α2肾上腺素受体结合后激活过氧化物酶体增殖物激活受体γ抑制LPS诱导的炎症反应
DOI：
10.1016/j.ejphar.2020.173733
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发表时间：
2021-01-09
影响因子：
5
通讯作者：
Miyawaki, Takuya
中科院分区：
文献类型：
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作者：
Fujimoto, Maki;Higuchi, Hitoshi;Miyawaki, Takuya
在过去的十年中，已发现右美托咪定（DEX）具有抗炎作用。然而，DEX的局部抗炎机制尚未完全阐明。一些细胞内炎症通路在炎症过程中导致负反馈。环加氧酶（考克斯）级联反应合成前列腺素（PGs），在炎症中起关键作用，但已知通过PGD（2）代谢物15-脱氧-δ-12，14-前列腺素J（2）（15 d-PGJ（2））及其受体过氧化物酶体增殖物激活受体γ（PPAR γ）的替代途径也具有抗炎特性。因此，我们假设DEX通过15 d-PGJ（2）和/或PPAR γ激活抑制LPS诱导的炎症反应，并评估DEX对这些反应的影响。将RAW264.7小鼠巨噬细胞样细胞与DEX预孵育，然后加入LPS以诱导炎症反应。测量细胞上清液中TNF α、IL-6、PGE（2）和15 d-PGJ（2）的浓度，并评价细胞中的PPAR γ和考克斯-2的基因表达。此外，我们评估了选择性α 2肾上腺素受体拮抗剂育亨宾或选择性过氧化物酶体增殖物激活受体γ拮抗剂T0070907是否逆转了DEX对LPS诱导的炎症反应的作用。DEX可抑制LPS诱导的TNF α、IL-6和PGE（2）的产生及考克斯-2 mRNA的表达，DEX的作用可被育亨宾逆转。另一方面，DEX显著增加15 d-PGJ（2）的产生和PPAR γ mRNA的表达，育亨宾逆转了DEX的这些作用。此外，T0070907逆转了DEX对细胞中TNF α（2）和IL-6产生的抗炎作用。这些结果表明，DEX通过与α 2肾上腺素受体结合后激活PPAR γ来抑制LPS诱导的炎症反应。
Over the past decade, dexmedetomidine (DEX) has been found to possess an anti-inflammatory effect. However, the local anti-inflammatory mechanism of DEX has not been fully clarified. Some intracellular inflammatory pathways lead to negative feedback during the inflammatory process. The cyclooxygenase (COX) cascade synthesizes prostaglandins (PGs) and plays a key role in inflammation, but is known to also have anti-inflammatory properties through an alternative route of a PGD(2) metabolite, 15-deoxy-delta-12,14-prostaglandin J(2) (15d-PGJ(2)), and its receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma). Therefore, we hypothesized that DEX inhibits LPS-induced inflammatory responses through 15d-PGJ(2) and/or PPAR gamma activation, and evaluated the effects of DEX on these responses. The RAW264.7 mouse macrophage-like cells were pre-incubated with DEX, followed by the addition of LPS to induce inflammatory responses. Concentrations of TNF alpha, IL-6, PGE(2), and 15d-PGJ(2) in the supernatants of the cells were measured, and gene expressions of PPAR gamma and COX-2 were evaluated in the cells. Furthermore, we evaluated whether a selective alpha(2) adrenoceptor antagonist, yohimbine or a selective PPAR gamma antagonist, T0070907, reversed the effects of DEX on the LPS-induced inflammatory responses. DEX inhibited LPS-induced TNF alpha, IL-6, and PGE(2) productions and COX-2 mRNA expression, and the effects of DEX were reversed by yohimbine. On the other hand, DEX significantly increased 15d-PGJ(2) production and PPAR gamma mRNA expression, and yohimbine reversed these DEX's effects. Furthermore, T0070907 reversed the anti-inflammatory effects of DEX on TNF alpha(2) and IL-6 productions in the cells. These results suggest that DEX inhibits LPS-induced inflammatory responses through PPAR gamma activation following binding to alpha(2) adrenoceptors.