Cannabinoid Receptor 2 Agonist JWH-015 Inhibits Interleukin-1β-Induced Inflammation in Rheumatoid Arthritis Synovial Fibroblasts and in Adjuvant Induced Arthritis Rat via Glucocorticoid Receptor
Cannabinoid Receptor 2 Agonist JWH-015 Inhibits Interleukin-1β-Induced Inflammation in Rheumatoid Arthritis Synovial Fibroblasts and in Adjuvant Induced Arthritis Rat via Glucocorticoid Receptor
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DOI：
10.3389/fimmu.2019.01027
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发表时间：
2019-05-08
影响因子：
7.3
通讯作者：
Ahmed, Salahuddin
中科院分区：
文献类型：
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作者：
Fechtner, Sabrina;Singh, Anil K.;Ahmed, Salahuddin
在类风湿性关节炎（RA）的治疗中，疼痛的管理是常规疗法未完全解决的优先事项。在本研究中，我们评估了大麻素受体2（CB 2）激动剂JWH-015的疗效，使用RA滑膜成纤维细胞（RASFs）从诊断为RA的患者和大鼠抗炎药诱导的关节炎（AIA）模型RA。用JWH-015（10-20 μ M）预处理人RASF显著抑制促炎细胞因子白细胞介素-1 β（IL-1 β）诱导IL-6和IL-8产生的能力以及炎性环氧合酶-2（考克斯-2）的细胞表达。JWH-015可有效降低IL-1 β诱导的人RASF中TAK 1（Thr 184/187）和JNK/SAPK的磷酸化。虽然使用siRNA方法敲低RASF中的CB 2减少了IL-1 β诱导的炎症，但JWH-015在不存在CB 2的情况下仍然有效地引发其抗炎作用，这表明了非典型或脱靶受体的作用。利用分子对接和分子动力学模拟的计算研究表明，JWH-105有利地结合糖皮质激素受体（GR）的结合姿势和相互作用类似于其众所周知的配体地塞米松。此外，使用siRNA敲低GR消除了JWH-015减少IL-1 β诱导的IL-6和IL-8产生的能力。在体内，给予JWH-015（5 mg/kg，在关节炎发作时每天腹膜内给药7天）显著改善大鼠的AIA。使用von Frey方法的疼痛评估研究显示，用JWH-015处理的AIA大鼠具有显著的抗伤害感受作用。此外，JWH-015处理抑制骨破坏，如从对所采集的关节的微CT扫描和骨分析所证明的，并且调节血清RANKL和OPG水平。总的来说，我们的研究结果表明，CB 2激动剂JWH-015部分通过GR发挥抗炎作用。这种化合物可以进一步作为非阿片类药物治疗RA的疼痛和组织破坏的辅助治疗进行测试。
Management of pain in the treatment of rheumatoid arthritis (RA) is a priority that is not fully addressed by the conventional therapies. In the present study, we evaluated the efficacy of cannabinoid receptor 2 (CB2) agonist JWH-015 using RA synovial fibroblasts (RASFs) obtained from patients diagnosed with RA and in a rat adjuvant-induced arthritis (AIA) model of RA. Pretreatment of human RASFs with JWH-015 (10-20 mu M) markedly inhibited the ability of pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) to induce production of IL-6 and IL-8 and cellular expression of inflammatory cyclooxygenase-2 (COX-2). JWH-015 was effective in reducing IL-1 beta-induced phosphorylation of TAK1 (Thr184/187) and JNK/SAPK in human RASFs. While the knockdown of CB2 in RASFs using siRNA method reduced IL-1 beta-induced inflammation, JWH-015 was still effective in eliciting its anti-inflammatory effects despite the absence of CB2, suggesting the role of non-canonical or an off-target receptor. Computational studies using molecular docking and molecular dynamics simulations showed that JWH-105 favorably binds to glucocorticoid receptor (GR) with the binding pose and interactions similar to its well-known ligand dexamethasone. Furthermore, knockdown of GR using siRNA abrogated JWH-015's ability to reduce IL-1 beta-induced IL-6 and IL-8 production. In vivo, administration of JWH-015 (5 mg/kg, daily i.p. for 7 days at the onset of arthritis) significantly ameliorated AIA in rats. Pain assessment studies using von Frey method showed a marked antinociception in AIA rats treated with JWH-015. In addition, JWH-015 treatment inhibited bone destruction as evident from micro-CT scanning and bone analysis on the harvested joints and modulated serum RANKL and OPG levels. Overall, our findings suggest that CB2 agonist JWH-015 elicits anti-inflammatory effects partly through GR. This compound could further be tested as an adjunct therapy for the management of pain and tissue destruction as a non-opioid for RA.