Xu Jihong, Storer Paul D, Chavis Janet A, Racke Michael K, Drew Paul D
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
J Neurosci Res. 2005 Aug 1;81(3):403-11. doi: 10.1002/jnr.20518.
The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). In the present study we investigated the effects of PPAR-alpha agonists on primary mouse microglia, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO production by cytokine-stimulated microglia in a dose-dependent manner. However, fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and ciprofibrate. In LPS-stimulated microglia, only fenofibrate and WY 14,643 significantly suppressed NO production. Additionally, PPAR-alpha agonists inhibited the secretion of the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, the RXR agonist 9-cis retinoic acid (9-cis RA) inhibited NO production by LPS-stimulated microglia. Furthermore, a combination of 9-cis RA and the PPAR-alpha agonist fenofibrate cooperatively inhibited NO production by these cells. A combination of these agonists also selectively inhibited the expression of proinflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 by LPS-stimulated microglia. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might have benefit as a therapy in MS, where activated microglia are believed to contribute to disease pathology.
过氧化物酶体增殖物激活受体α（PPAR-α）在脂质代谢和炎症中起关键作用。最近，我们证明给予PPAR-α激动剂吉非贝齐和非诺贝特可抑制实验性自身免疫性脑脊髓炎（EAE）的临床症状，EAE是多发性硬化症（MS）的动物模型。在本研究中，我们研究了PPAR-α激动剂对原代小鼠小胶质细胞的影响，小胶质细胞是一种与MS和EAE病理相关的细胞类型。我们的研究表明，PPAR-α激动剂环丙贝特、非诺贝特、吉非贝齐和WY 14,643均以剂量依赖的方式抑制细胞因子刺激的小胶质细胞产生NO。然而，非诺贝特和WY 14,643比吉非贝齐和环丙贝特是更有效的抑制剂。在LPS刺激的小胶质细胞中，只有非诺贝特和WY 14,643能显著抑制NO的产生。此外，PPAR-α激动剂抑制LPS刺激的小胶质细胞分泌促炎细胞因子IL-1β、TNF-α、IL-6和IL-12 p40以及趋化因子MCP-1。视黄酸X受体（RXR）与PPAR-α受体发生物理相互作用，形成的异二聚体调节PPAR反应基因的表达。有趣的是，RXR激动剂9-顺式视黄酸（9-cis RA）抑制LPS刺激的小胶质细胞产生NO。此外，9-顺式视黄酸和PPAR-α激动剂非诺贝特联合使用可协同抑制这些细胞产生NO。这些激动剂联合使用还能选择性抑制LPS刺激的小胶质细胞表达包括IL-1β、TNF-α和IL-6在内的促炎细胞因子。总的来说，这些结果提示PPAR-α和RXR激动剂作为一种治疗MS的方法可能有益，因为在MS中活化的小胶质细胞被认为会导致疾病病理改变。
