Role of T cells and PPARgamma in Graves' orbital fibroblast adipogenesis

描述（由申请人提供）：甲状腺相关性眼病（TAO，又称Graves眼病）是一种严重的自身免疫性疾病，涉及眼眶组织炎症。眼眶组织主要由T淋巴细胞浸润，含有促炎细胞因子和前列腺素。TAO的一个特征是眼窝脂肪增加，使眼球脱离眼窝（眼球突出）。TAO会毁容，并可能导致失明。脂肪前轨道成纤维细胞是这一过程中的关键效应细胞。眼眶炎症被认为驱使它们分化为脂肪细胞。诱导这种分化的炎症信号仍然是TAO的一个重要方面，但研究很少。脂肪细胞分化被认为主要由一种称为过氧化物酶体增殖物激活受体（PPARgamma）的转录因子控制。我们的研究表明，人眼眶成纤维细胞高度表达PPARgamma，并且天然（15d-PGJ2）和合成（如胰岛素增敏药物罗格列酮）的PPARgamma配体都能诱导一部分Graves眼眶成纤维细胞分化为脂肪细胞。我们令人信服的新数据表明，来自Graves患者的循环T淋巴细胞高度表达前列腺素生成酶环氧化酶-2 （Cox-2）并产生PPARgamma配体15d-PGJ2。此外，Graves’T细胞驱动一个表达TAO的PPARgamma成纤维细胞亚群转化为脂肪细胞。这些令人兴奋的数据首次证明了人类T细胞产生功能性PPARgamma配体，并支持眼眶炎症过程驱动脂肪形成。我们将验证的总体假设是，Graves’T淋巴细胞产生PPARgamma配体，诱导表达PPARgamma的眶成纤维细胞亚群分化为脂肪细胞。以下三个问题提出的具体目标将回答，以检验整体假设。目的1：格雷夫斯病人类T淋巴细胞是否具有高表达Cox-2和产生前列腺素（例如15d-PGJ2）作为PPARgamma配体的能力？目的2：格雷夫斯眼眶成纤维细胞向脂肪细胞分化的能力是否依赖于促脂肪生成转录因子PPARgamma？目的3:Thy1+和Thy1- Graves眼眶成纤维细胞之间的差异决定了为什么只有ThyT成纤维细胞分化为脂肪细胞？这些研究将有助于描述炎症细胞和刺激眼眶成纤维细胞分化为脂肪细胞的途径。这一新信息将允许开发新的方法来控制炎症和眼眶成纤维细胞的病理分化，这对TAO和其他涉及脂肪沉积的疾病很重要。

DESCRIPTION (provided by applicant): Thyroid associated ophthalmopathy (TAO, also called Graves' ophthalmopathy) is a serious autoimmune disease involving orbital tissue inflammation. Orbital tissue is infiltrated mainly by T lymphocytes and contains proinflammatory cytokines and prostaglandins. A hallmark of TAO is an increase in orbital fat that pushes the eye out of the orbit (proptosis). TAO is disfiguring and may lead to blindness. Pre-adipocyte orbital fibroblasts are key effector cells in this process. Orbital inflammation is postulated to drive their differentiation to fat cells called adipocytes. The inflammatory signals that induce this differentiation remain an important, yet poorly studied aspect of TAO. Adipocytic differentiation is believed to be mainly controlled by a transcription factor called peroxisome proliferator activated receptor gamma (PPARgamma). Our research shows that human orbital fibroblasts highly express PPARgamma and that both natural (15d-PGJ2) and synthetic (e.g. the insulin-sensitizing drugs rosiglitazone) PPARgamma ligands induce a subset of Graves' orbital fibroblasts to differentiate to adipocytes. Our compelling new data show that circulating T lymphocytes from Graves' patients' highly express the prostaglandin-generating enzyme cycloxygenase-2 (Cox-2) and produce the PPARgamma ligand 15d-PGJ2. Moreover, Graves' T cells drive a subset of PPARgamma expressing TAO fibroblasts to adipocytes. These exciting data are the first to demonstrate that human T cells produce a functional PPARgamma ligand and supports that the process of orbital inflammation drives adipogenesis. The overall hypothesis we will test is that Graves' T lymphocytes produce a PPARgamma ligand that induces a subset of PPARgamma expressing orbital fibroblasts to differentiate to adipocytes. The following three questions posed as specific aims will be answered to test the overall hypothesis. Aim 1: Are Graves' disease human T lymphocytes unique in their ability to highly express Cox-2 and produce prostaglandins (e.g. 15d-PGJ2) that act as PPARgamma ligands? Aim 2: Is the ability of Graves' orbital fibroblasts to differentiate to adipocytes dependent on the pro-adipogenic transcription factor PPARgamma? Aim 3: What are the differences between Thy1+ and Thy1- Graves' orbital fibroblasts that determine why only ThyT fibroblasts differentiate to adipocytes? These studies will help delineate the inflammatory cells and pathways that incite orbital fibroblast differentiation to adipocytes. This new information will permit the development of new approaches to control inflammation and the pathologic differentiation of orbital fibroblasts important for TAO and other diseases that involve fat deposition.