The role of Mcl-1 in the macrophages and RA

描述（由申请方提供）：单核细胞/巨噬细胞对于宿主免疫应答至关重要，并参与类风湿性关节炎（RA）的发病机制。我们证明了PI 3 K/Akt-1依赖性Mcl-1表达对巨噬细胞存活至关重要。PI 3 K/Akt的抑制降低了Mcl-1的表达，导致通过线粒体途径介导的细胞凋亡。通过反义寡核苷酸强制下调Mcl-1也诱导细胞凋亡，表明Mcl-1对巨噬细胞活力至关重要。此外，我们的初步数据表明，Mcl-1也可能是由JAK/STAT途径在人类巨噬细胞的调节。因此，我们建议确定PI 3 K/Akt和JAK/STAT 3通路有助于调节巨噬细胞中Mcl-1的机制。此外，我们将通过检查Mcl-1与促凋亡分子（如巨噬细胞中的Bax）的相互作用来确定Mcl-1保护巨噬细胞的机制，以描述Mcl-1消融后发生的线粒体功能障碍的机制。我们的初步数据表明，Mcl-1可能在维持RA滑膜巨噬细胞的活力中起重要作用。此外，我们的初步数据显示，在体外，Mcl-1是高表达的RA，骨关节炎（OA），滑膜成纤维细胞相比。Mcl-1在佐剂性关节炎（AIA）大鼠滑膜中也有强表达。因此，我们建议表征Mcl-1在RA关节中的表达和功能，检查巨噬细胞和滑膜成纤维细胞。我们建议确定是否强制下调Mcl-1将改善实验性关节炎，这将表明，Mcl-1是一个贡献者的开始和/或进展的关节炎。因此，本研究将阐明Mcl-1在巨噬细胞中的表达调控机制及其新功能。进一步的研究建议描绘潜在的细胞类型之间的特定差异巨噬细胞和正常，骨关节炎和类风湿性关节炎滑膜成纤维细胞。这些实验将提供有关Mcl-1的新作用的新的重要信息，这可能会提供见解，从而导致RA患者的治疗方法的改进。

DESCRIPTION (provided by applicant): Monocytes/macrophages are vital for host-immune responses and have been implicated in the pathogenesis of rheumatoid arthritis (RA). We demonstrated that PI3K/Akt-1-dependent Mcl-1 expression is vital for macrophage survival. Suppression of PI3K/Akt reduced Mcl-1 expression, resulting in apoptosis mediated through the mitochondrial pathway. Forced downregulation of Mcl-1 through antisense oligonucleotides also induced apoptosis, demonstrating that Mcl-1 is essential for macrophage viability. Further, our preliminary data suggested that Mcl-1 may also be regulated by the JAK/STAT pathway in human macrophages. Therefore, we propose to determine the mechanisms by which the PI3K/Akt and JAK/STAT3 pathways contribute to the regulation of Mcl-1 in macrophages. Additionally, we will identify the mechanism by which Mcl-1 protects macrophages by examining the interaction of Mcl-1 with pro-apoptotic molecules, such as Bax in macrophages to delineate the mechanism of mitochondrial dysfunction that occurs following Mcl-1 ablation. Our preliminary data suggests that Mcl-1 may be important in the in maintaining the viability of RA synovial macrophages. Additionally, our preliminary data has revealed that in vitro, Mcl-1 was highly expressed in RA, compared to osteoarthritis (OA), synovial fibroblasts. Mcl-1 was also strongly expressed in the synovium of rats with adjuvant-induced arthritis (AIA). Therefore, we propose to characterize the expression and function of Mcl-1 in the RA joint, examining macrophages and synovial fibroblasts. We propose to determine if the forced downregulation of Mcl-1 will ameliorate experimental arthritis, which would indicate that Mcl-1 is a contributor to the initiation and/or progression of arthritis. Thus, this proposal will delineate the mechanisms regulating the expression and the novel functions of Mcl-1 in macrophages. Further studies are proposed to delineate potential cell type-specific differences between macrophages and normal, osteoarthritis and rheumatoid arthritis synovial fibroblasts. These experiments will provide new and important information concerning the novel role of Mcl-1, which may provide insights that will lead to the development of improved therapy for patients with RA.