The Role of Mcl-1 in the Macrophages and RA

Project: Research project

Project Details

Description

Monocytes/macrophages are vital for host-immune responses and have been implicated in the pathogenesis ofrheumatoid arthritis (RA). We demonstrated that PI3K/Akt-l-dependent Mcl-1 expression is vital formacrophage survival. Suppression of PI3K/Akt reduced Mcl-1 expression, resulting in apoptosis mediatedthrough the mitochondrial pathway. Forced downregulation of Mcl-1 through antisense oligonucleotides alsoinduced apoptosis, demonstrating that Mcl-1 is essential for macrophage viability. Further, our preliminarydata 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 pathwayscontribute to the regulation of Mcl-1 in macrophages. Additionally, we will identify the mechanism by whichMcl-1 protects macrophages by examining the interaction of Mcl-1 with pro-apoptotic molecules, such asBax in macrophages to delineate the mechanism of mitochondrial dysfunction that occurs following Mcl-1ablation. Our preliminary data suggests that Mcl-1 may be important in the in maintaining the viability of RAsynovial macrophages. Additionally, our preliminary data has revealed that in vitro, Mcl-1 was highlyexpressed in RA, compared to osteoarthritis (OA), synovial fibroblasts. Mcl-1 was also strongly expressed inthe synovium of rats with adjuvant-induced arthritis (AIA). Therefore, we propose to characterize theexpression and function of Mcl-1 in the RA joint, examining macrophages and synovial fibroblasts. Wepropose to determine if the forced downregulation of Mcl-1 will ameliorate experimental arthritis, whichwould indicate that Mcl-1 is a contributor to the initiation and/or progression of arthritis. Thus, this proposalwill 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 andnormal, osteoarthritis and rheumatoid a
StatusFinished
Effective start/end date1/1/0312/31/08

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (5 R01 AR049217-05)

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