The Role of Raf Kinase Inhibitor Protein in Rheumatoid Fibroblast-like Synoviocytes Invasiveness and Cytokine and Matrix
- PDF / 361,384 Bytes
- 10 Pages / 595.276 x 790.866 pts Page_size
- 54 Downloads / 176 Views
The Role of Raf Kinase Inhibitor Protein in Rheumatoid Fibroblast-like Synoviocytes Invasiveness and Cytokine and Matrix Metalloproteinase Expression Joong Kyong Ahn,1 Ji-Won Hwang,2 Eun-Kyung Bae,3 Jaejoon Lee,2 Chan Hong Jeon,4 Eun-Mi Koh,2 and Hoon-Suk Cha2,5
Abstract—Fibroblast-like synoviocytes (FLS) play an important role in the pathogenesis of rheumatoid arthritis. Raf kinase inhibitor protein (RKIP) negatively regulates the Raf/MEK/ ERK and NF-κB pathway. The role of RKIP in rheumatoid FLS is unknown. The purpose of the present study was to investigate the function of RKIP in rheumatoid FLS. Rheumatoid FLS were transfected with either RKIP-expressing plasmids or RKIP small interfering RNA (siRNA). RKIP protein was detected in rheumatoid synovial tissue (ST) and FLS. RKIP overexpression significantly decreased IL-6 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP overexpression also showed a decreased trend in IL-8, MMP-1, and MMP-3 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP silencing resulted in significantly increased MMP-1 and MMP-3 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP silencing also increased IL-6 and IL-8 mRNA expression in TNF-α-stimulated rheumatoid FLS, but this increase did not reach statistical significance. TNF-αinduced ERK and NF-κB activation was suppressed in FLS with RKIP overexpression. RKIP silencing resulted in a significantly higher invasion index in TNF-α-stimulated rheumatoid FLS compared to controls. These results suggest that RKIP might be a potential therapeutic target for rheumatoid arthritis. KEY WORDS: raf kinase inhibitor protein; rheumatoid arthritis; fibroblast-like synoviocytes; matrix metalloproteinase; cytokines.
tion of bone and cartilage. Pannus formation and bone erosions in RA joints are mediated by pronounced tumor-like expansions of fibroblast-like synoviocytes (FLS) [1, 2]. Rheumatoid FLS undergo a phenotypical transformation that includes unregulated growth, loss of contact inhibition, and a pattern of oligoclonal expansion [2–4]. Also, rheumatoid FLS produce inflammatory mediators, such as IL-6 and IL-8, and matrix degrading enzymes, including matrix metalloproteinase (MMP)-1 and MMP-3 [2, 3]. The role of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) in RA has been explored extensively. These kinases and transcription factors regulate the expression of inflammatory cytokines such as IL-1, IL-6, IL-8, TNF-α, and MMPs in RA. The extracellular signal-regulated kinases (ERKs), C-Jun-N-terminal kinase (JNK) and p38 are constitutively expressed in RA synovium as well as rheumatoid FLS [5].
INTRODUCTION Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease characterized by synovial inflammation, hyperplasia of the synovial tissues, and destruc1
Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 2 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul, 135
Data Loading...
