Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner.
Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner.
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DOI：
10.1186/s13075-015-0845-5
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发表时间：
2015-11-14
影响因子：
4.9
通讯作者：
Straub RH
中科院分区：
文献类型：
--
作者：
Lowin T;Apitz M;Anders S;Straub RH
内源性大麻素系统调节免疫细胞和成纤维细胞等间充质细胞的功能，在类风湿关节炎(RA)的软骨破坏中起重要作用。本研究的目的是确定N-酰乙醇胺(AEA)、棕榈酰乙醇胺(PEA)和油乙醇胺(OEA)在体外(人材料)和体内(小鼠模型)对关节炎炎症的几个特征的影响。免疫荧光法和免疫印迹法检测大麻素受体及相关酶。采用双抗体夹心法检测细胞因子和基质金属蛋白酶-3的表达。蛋白质组图谱检测细胞内信号转导蛋白。用CTB试剂定量检测细胞增殖。粘附力采用xCELigence系统进行评估。在小鼠出现II型胶原关节炎后，每天用FAAH抑制剂JNJ1661010(20 mg/kg)或赋形剂治疗。经AEA、PEA和OEA治疗后，滑膜细胞和滑膜成纤维细胞中IL-6、IL-8和MMP3表达下调。在SFS中，这是由于TRPV1和TRPA1以COX-2依赖的方式激活。抑制FAAH可增加AEA对原代滑膜细胞的作用，但对SFS的作用不明显。OEA和PEA对SFS的影响可被FAAH抑制减弱。在OASF中，AEA以CB1依赖的方式增加对纤维连接蛋白的黏附。此外，内源性大麻素的升高可以改善胶原蛋白诱导的小鼠关节炎。N-乙酰乙醇胺在SFS中具有抗炎作用。FAAH/COX-2双重抑制剂，增加N-乙酰乙醇胺水平，伴随Trp通道脱敏，可能是抑制滑膜细胞促炎介质产生和减少侵蚀的良好候选药物。本文的在线版本(doi：10.1186/s13075-015-0845-5)包含补充材料，授权用户可以使用。
The endocannabinoid system modulates function of immune cells and mesenchymal cells such as fibroblasts, which contribute to cartilage destruction in rheumatoid arthritis (RA). The aim of the study was to determine the influence of N-acylethanolamines anandamide (AEA), palmitoylethanolamine (PEA) and oleylethanolamine (OEA) on several features of arthritic inflammation in vitro (human material) and in vivo (a mouse model). Immunofluorescence and western blotting were used to detect cannabinoid receptors and related enzymes. Cytokines and MMP-3 were measured by ELISA. Intracellular signaling proteins were detected by proteome profiling. Proliferation was quantified by CTB reagent. Adhesion was assessed by the xCELLigence system. After onset of collagen type II arthritis, mice were treated daily with the FAAH inhibitor JNJ1661010 (20 mg/kg) or vehicle. IL-6, IL-8 and MMP-3 (determined only in synovial fibroblasts (SFs)) were downregulated in primary synoviocytes and SFs of RA and OA after AEA, PEA and OEA treatment. In SFs, this was due to activation of TRPV1 and TRPA1 in a COX-2-dependent fashion. FAAH inhibition increased the efficacy of AEA in primary synoviocytes but not in SFs. The effects of OEA and PEA on SFs were diminished by FAAH inhibition. Adhesion to fibronectin was increased in a CB1-dependent manner by AEA in OASFs. Furthermore, elevation of endocannabinoids ameliorated collagen-induced arthritis in mice. N-acylethanolamines exert anti-inflammatory effects in SFs. A dual FAAH/COX-2 inhibitor, increasing N-acylethanolamine levels with concomitant TRP channel desensitization, might be a good candidate to inhibit the production of proinflammatory mediators of synovial cells and to reduce erosions. The online version of this article (doi:10.1186/s13075-015-0845-5) contains supplementary material, which is available to authorized users.