Estrogenic Regulation of Inflammation Related to TMJD

描述(由申请人提供)：我们的长期目标是识别和表征类固醇激素影响人类疾病发病和/或严重程度的基因。这项应用的目的是确定巨噬细胞中受雌激素停用影响的基因，如产后和更年期，该基因在免疫过程中发挥作用。我们的中心假设是，雌激素浓度的变化直接调节Ig G Fcγ受体III-A(CD16A)的表达，从而调节促炎症细胞因子的产生和/或巨噬细胞对受体结合的释放。这一假说是基于我们最近在体外发现的：1)去除雌激素后，巨噬细胞样THP-1细胞和原代外周血巨噬细胞中FcγRIIIA转录水平增加；2)观察到的增加依赖于转录。假说 还包括来自另一个实验室的数据，该数据表明Fc Gamma RIIIA通过抗Fc Gamma Rill结合 单抗可刺激巨噬细胞释放肿瘤坏死因子-α和白介素1-α。Fc-Gamma RIIIA是一种选择性结合自身免疫性疾病中重要的类风湿因子(RF)的免疫球蛋白G分子的受体。总之，这些数据表明，RF结合该受体刺激类风湿性关节炎和相关的颞下颌关节紊乱病(TMJD)中细胞因子的释放。为了验证我们的中心假设，目的是研究在调节Fc-Gamma RIIIA表达后，刺激的巨噬细胞产生和释放巨噬细胞细胞因子的特征。在使用各种雌激素和Fc-Gamma RIIIA反义治疗改变Fc-Gamma RIIIA表达水平后，将检测TNF-α和IL-1α。目标二将重点介绍Fc-Gamma-RIIIA交联剂诱导细胞因子产生和/或释放的机制。将确定信号转导途径和激活的转录因子以及调节的肿瘤坏死因子-α和白介素1-α启动子序列。目的三探讨雌激素调节巨噬细胞Fc-γRIIIA基因转录的机制。雌激素受体ERα和/或ERβ的功能将直接通过药理学(如抗雌激素)和通过Fc-Gamma RIIIA启动子的突变研究来解决。

DESCRIPTION (provided by applicant): Our long-range goal is to identify and characterize genes through which steroidal hormones affect the onset and/or severity of human disease. The objective of this application is to determine a gene in macrophages affected by estrogen withdrawal, as seen post-partum and at menopause, that functions in immune processes. Our central hypothesis is that changes in estrogen concentrations directly regulate IgG Fc gamma receptor III-A (CD16a) expression resulting in a modulation of pro-inflammatory cytokine production and/or release from macrophages upon receptor binding. This hypothesis is based on our recent findings in vitro that 1) the level of Fc gamma RIIIA transcript increased in macrophage-like THP-1 cells and in primary, peripheral blood macrophages after estrogen removal and 2) that the observed increase was dependent on transcription. The hypothesis also includes data from another lab that binding of Fc gamma RIIIA by anti-Fc gamma RIll monoclonal antibodies stimulates macrophage TNF-alpha and IL-1 alpha release. Fc gamma RIIIA is a receptor that selectively binds IgG molecules, an important rheumatoid factor (RF) in auto-immune disease. Collectively, these data suggest that RF binding of this receptor stimulates cytokine release in rheumatoid arthritis and associated temporomandibular joint disorders (TMJD). To test our central hypothesis aim one will characterize macrophage cytokine production and release from stimulated macrophages after modulating Fc gamma RIIIA expression. TNF-alpha and IL-1 alpha will be measured after changing Fc gamma RIIIA expression levels using various estrogen and Fc gamma RIIIA antisense treatments. Aim two will focus on the mechanism inducing cytokine production and/or release upon Fc gamma RIIIA crosslinking. Signal transduction pathways and activated transcription factors will be identified as well as regulatory TNF-alpha and IL-1 alpha promoter sequences. Aim three will address the mechanism by which estrogen regulates Fc gamma RIIIA gene transcription in macrophages. The function of estrogen receptors ER alpha and/or ER beta will be directly addressed pharmacologically (e.g., antiestrogen) and through mutation studies of the Fc gamma RIIIA promoter.