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病和/或严重程度的基因。本应用的目的是确定巨噬细胞中受雌激素停药影响的基因，如产后和更年期，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 （CD16a）的表达，从而调节促炎细胞因子的产生和/或巨噬细胞在受体结合后的释放。这一假设是基于我们最近在体外的发现：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转录水平升高，2)所观察到的升高依赖于转录。假设

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.