Mcl-1 is essential for the survival of synovial fibroblasts in rheumatoid arthritis.
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.
Liu
Hongtao
H
Division of Rheumatology, Northwestern University Feinberg School of Medicine and The Jesse Brown Veterans Affairs Chicago Heathcare System, IL 60611, USA.
Eksarko
Polikseni
P
Temkin
Vladislav
V
Haines
G Kenneth
GK
Perlman
Harris
H
Koch
Alisa E
AE
Thimmapaya
Bayar
B
Pope
Richard M
RM
D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000473:pathology*; D002470:Cell Survival; D005347:Fibroblasts / Q000737:chemistry / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D013582:Synovial Fluid / Q000737:chemistry / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
D007375:Interleukin-1; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha