Mcl-1 Is Essential for the Survival of Synovial Fibroblasts in Rheumatoid Arthritis

• Published in: Journal of Immunology 2005-12, Vol.175 (12), p.8337-8345
• Main Authors: Liu, Hongtao, Eksarko, Polikseni, Temkin, Vladislav, Haines, G. Kenneth, III, Perlman, Harris, Koch, Alisa E, Thimmapaya, Bayar, Pope, Richard M
• Format: Article
• Language: English
• Subjects: Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - pathology; Cell Survival; Fibroblasts - chemistry; Fibroblasts - pathology; Gene Expression Regulation - drug effects; Humans; Inflammation; Interleukin-1 - pharmacology; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - analysis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Proto-Oncogene Proteins c-bcl-2 - analysis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - physiology; Synovial Fluid - chemistry; Synovial Fluid - cytology; Tumor Necrosis Factor-alpha - drug effects
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.175.12.8337

Mcl-1 is a Bcl-2-family, antiapoptotic molecule that is critical for the survival of T and B lymphocytes and macrophages; however, its role in nonhemopoietic cells remains to be fully elucidated. The current study focuses on the role of Mcl-1 in rheumatoid arthritis (RA). Mcl-1 was strongly expressed in the synovial lining and was increased in the sublining fibroblasts of patients with RA, compared with control synovial tissue. The expression of Mcl-1 in sublining fibroblasts correlated with the degree of inflammation and TNF-alpha, and IL-1beta treatment of cultured synovial fibroblasts resulted in the increased expression of Mcl-1 at the mRNA and protein levels. Mcl-1 was critical for the survival of RA synovial fibroblasts, because the forced reduction of Mcl-1 using a Mcl-1 antisense-expressing adenoviral vector induced apoptotic cell death, which was mediated through Bax, Bak, and Bim. These observations document a critical role for Mcl-1 in protecting against apoptosis in RA and suggest that Mc1-1 is a potential therapeutic target in this disease.