Regulation of Mcl-1 expression in rheumatoid arthritis synovial macrophages

Hongtao Liu, Qi Quan Huang, Bo Shi, Polikseni Eksarko, Vladislav Temkin, Richard M. Pope*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Objective. Resistance to apoptosis may be an important mechanism contributing to the persistence of rheumatoid arthritis (RA). This study was undertaken to characterize the expression, regulation, and function of the antiapoptotic Bcl-2 family member Mcl-1 in macrophages isolated from the joints of patients with RA. Methods. Mononuclear cells were isolated from the synovial fluid (SF) of patients with MA. Mcl-1 expression was documented by intracellular staining of CD14+ cells using flow cytometry, and by real-time polymerase chain reaction or immunoblot analysis of isolated macrophages. The expression of Mcl-1 was suppressed with small interfering RNA (siRNA) or chemical inhibitors of the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt-1 and signal transducer and activator of transcription 3 (STAT-3) pathways. Apoptosis was defined by the loss of mitochondrial transmembrane potential and by DNA fragmentation. Results. The expression of Mcl-1 was increased in CD14+ macrophages from the SF of patients with MA compared with normal in vitro-differentiated macrophages. Inhibition of the PI 3-kinase/Akt-1 or STAT-3 pathways significantly reduced the percentage of CD14+ cells within the SF and resulted in the reduction of Mcl-1 and the induction of apoptosis of synovial macrophages. Transfection of RA synovial macrophages with Mcl-1 siRNA resulted in apoptotic cell death. Conclusion. Mcl-1 is critical for the survival of macrophages in the joints of patients with MA, and is therefore a potential therapeutic target in this disease.

Original languageEnglish (US)
Pages (from-to)3174-3181
Number of pages8
JournalArthritis and rheumatism
Volume54
Issue number10
DOIs
StatePublished - Oct 2006

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Immunology and Allergy
  • Rheumatology
  • Immunology

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