Peroxisome proliferator-activated receptor γ (PPARγ) and immunoregulation:: Enhancement of regulatory T cells through PPARγ-dependent and -independent mechanisms
Peroxisome proliferator-activated receptor γ (PPARγ) and immunoregulation:: Enhancement of regulatory T cells through PPARγ-dependent and -independent mechanisms
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DOI：
10.4049/jimmunol.178.7.4129
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发表时间：
2007-04-01
影响因子：
4.4
通讯作者：
Clark, Robert B.
中科院分区：
文献类型：
--
作者：
Wohlfert, Elizabeth A.;Nichols, Frank C.;Clark, Robert B.
过氧化物酶体增殖物激活受体(PPAR)γ是一种核激素受体，其主要特征是对胰岛素代谢有影响。用于治疗人类2型糖尿病的PPAR伽马配体也下调大多数免疫系统细胞，包括APC和致病T细胞。这些效应被认为是PPAR伽马配体治疗自身免疫动物模型的有效性的基础，导致了人类自身免疫治疗潜力的预测。然而，PPARγ配体与CD4(+)CD25(+)调节性T细胞(Treg)之间的关系尚未被研究。具体地说，还没有研究探讨Tregs在介导PPAR伽马配体体内免疫调节效应中的作用，也没有研究在缺乏Tregs的情况下使用PPAR伽马配体来治疗自身免疫。我们现在描述了环格列酮，一类噻唑烷二酮类的PPAR伽马配体，与小鼠自然Tregs(NTregs)和诱导性Tregs(ITregs)之间的新关系。在体外，齐格列酮以PPAR伽马不依赖的方式显著促进iTregs的产生。令人惊讶的是，与目前的范式相反，我们发现，在移植物抗宿主疾病的模型中，环格列酮的免疫治疗作用需要表达PPAR伽马的nTregs的存在。总体而言，我们的结果表明，与其对免疫系统其他细胞的下调作用不同，齐格列酮对iTregs和nTregs都有增强作用，这一发现可能对使用PPAR伽马配体治疗人类自身免疫性疾病具有重要意义。
Peroxisome proliferator-activated receptor (PPAR)gamma is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism. PPAR gamma ligands, used to treat human type 2 diabetes, also down-regulate most immune system cells including APCs and pathogenic T cells. These effects putatively underlie the efficacy of PPAR gamma ligands in treating animal models of autoimmunity, leading to projections of therapeutic potential in human autoimmunity. However, the relationship between PPAR gamma ligands and CD4(+)CD25(+) regulatory T cells (Tregs) has not been examined. Specifically, no studies have examined the role of Tregs in mediating the in vivo immunoregulatory effects of PPAR gamma ligands, and there have been no investigations of the use of PPAR gamma ligands to treat autoimmunity in the absence of Tregs. We now characterize the novel relationship between ciglitazone, a thiazolidinedione class of PPAR gamma ligand, and both murine natural Tregs (nTregs) and inducible Tregs (iTregs). In vitro, ciglitazone significantly enhances generation of iTregs in a PPAR gamma-independent manner. Surprisingly, and contrary to the current paradigm, we find that, in a model of graft-vs-host disease, the immunotherapeutic effect of ciglitazone requires the presence of nTregs that express PPAR gamma. Overall, our results indicate that, unlike its down-regulatory effect on other cells of the immune system, ciglitazone has an enhancing effect on both iTregs and nTregs, and this finding may have important implications for using PPAR gamma ligands in treating human autoimmune disease.