The Role of Mcl-1 in the Macrophages and RA

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 arthritis synovial fibroblasts. These experiments will provide new andimportant information concerning the novel role of Mcl-1, which may provide insights that will lead to thedevelopment of improved therapy for patients with RA.PERFORMANCESITE(S) (organization,city, state)Northwestern University Medical SchoolDepartment of Medicine, Division of Rheumatology303 E Chicago AveWard 3-315Chicago, IL 60611KEY PERSONNEL. See instructions.Usecontinuation pages as needed toprovidetherequiredinformationintheformatshownbelow. StartwithPrincipalInvestigatorL istallotherkeypersonnelinalphabeticaol rder,lastnamefirst.Name Organization Roleon ProjectRichard M. Pope, MD Northwestern University PIHongtao Liu, MD PhD Northwestern University Co-investigatorHarris Perlman, PhD Northwestern University Co-investigatorG. Kenneth Haines, MD Northwestern University Co-investigatorDisclosure Permission Statement. Applicableto SBIR/STTROnly. See instructions.[] Yes [_ No PHS 398 (Rev. 05/01) Page2 Form Page 2. Principal InvestigatodProgram Director (Last, first, middle): Pope, Richard, M The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANTTABLE OF CONTENTS Page NumbersFace Page.................................................................................................................................................. 1Description