Transcriptional Modulation of the Immune Response by Peroxisome Proliferator-Activated Receptor-α Agonists in Autoimmune Disease
Transcriptional Modulation of the Immune Response by Peroxisome Proliferator-Activated Receptor-α Agonists in Autoimmune Disease
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DOI：
10.4049/jimmunol.0713927
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发表时间：
2009-04-01
影响因子：
4.4
通讯作者：
Racke, Michael K.
中科院分区：
文献类型：
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作者：
Gocke, Anne R.;Hussain, Rehana Z.;Racke, Michael K.
过氧化物酶体增殖物激活受体 α (PPAR α) 激动剂已被证明对实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症 (MS) 动物模型）具有治疗效果。在这项研究中，我们研究了 PPAR α 激动剂吉非贝齐诱导免疫偏差并保护小鼠免受 EAE 的机制。我们证明，在体外和直接离体条件下，用吉非罗齐治疗可增加 Th2 转录因子 GATA-3 的表达并降低 Th1 转录因子 T-bet 的表达。这些变化与核 PPAR α 表达的增加相关。此外，PPARα激动剂对EAE的保护作用被证明部分依赖于IL-4并且以受体依赖性方式发生。首次证明PPARα可以调节IL-4和IL-5基因，并在类固醇受体辅激活因子1存在的情况下结合IL-4启动子，表明PPARα可以直接反式激活IL-4基因。最后，PPAR α 激动剂的治疗性给药改善了临床上确定的 EAE，这表明 PPAR α 激动剂可能为免疫介导的炎症性疾病提供治疗选择。免疫学杂志，2009，182：4479-4487。
Peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonists have been shown to have a therapeutic benefit in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). In this study, we investigated the mechanism by which the PPAR alpha agonist gemfibrozil induces immune deviation and protects mice from EAE. We demonstrated that treatment with gemfibrozil increases expression of the Th2 transcription factor GATA-3 and decreases expression of the Th1 transcription factor T-bet in vitro and directly ex vivo. These changes correlated with an increase in nuclear PPAR alpha expression. Moreover, the protective effects of PPAR alpha agonists in EAE were shown to be partially dependent on IL-4 and to occur in a receptor-dependent manner. PPAR alpha was demonstrated, for the first time, to regulate the IL-4 and IL-5 genes and to bind the IL-4 promoter in the presence of steroid receptor coactivator-1, indicating that PPAR alpha can directly transactivate the IL-4 gene. Finally, therapeutic administration of PPAR alpha agonists ameliorated clinically established EAE, suggesting that PPAR alpha agonists may provide a treatment option for immune-mediated inflammatory diseases. The Journal of Immunology, 2009, 182: 4479-4487.