Estrogenic Regulation of Inflammation Related to TMJD

描述（由申请人提供）：我们的长期目标是鉴定和表征类固醇激素影响人类疾病发作和/或严重程度的基因。 本申请的目的是确定受雌激素戒断影响的巨噬细胞中的基因，如产后和绝经期所见，其在免疫过程中起作用。 我们的中心假设是雌激素浓度的变化直接调节IgG Fc γ受体III-A（CD 16 a）的表达，从而调节促炎细胞因子的产生和/或受体结合后巨噬细胞的释放。 该假设基于我们最近的体外发现，即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Fc γ RIIIA转录物的水平增加，2）观察到的增加依赖于转录。 的假设 还包括来自另一个实验室的数据，即抗Fc γ RIII与Fc γ RIIIA的结合 单克隆抗体刺激巨噬细胞TNF-α和IL-1 α释放。 Fc γ RIIIA是一种选择性结合IgG分子的受体，IgG分子是自身免疫疾病中的一种重要类风湿因子（RF）。 总的来说，这些数据表明，RF结合这种受体刺激类风湿性关节炎和相关的颞下颌关节疾病（TMJD）的细胞因子释放。 为了检验我们的中心假设，将表征在调节Fc γ RIIIA表达后巨噬细胞细胞因子的产生和从刺激的巨噬细胞的释放。 使用各种雌激素和Fc γ RIIIA反义治疗改变Fc γ RIIIA表达水平后，测量TNF-α和IL-1 α。 目的二将集中于在Fc γ RIIIA交联时诱导细胞因子产生和/或释放的机制。 将鉴定信号转导途径和活化的转录因子以及调节性TNF-α和IL-1 α启动子序列。 目的三将阐明雌激素调节巨噬细胞中Fc γ RIIIA基因转录的机制。 雌激素受体ER α和/或ER β的功能将被直接解决，例如，抗雌激素）和通过Fc γ RIIIA启动子的突变研究。

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.