The first two authors contributed equally to this study.
Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritis
Article first published online: 14 SEP 2011
© 2011 The Authors. International Journal of Rheumatic Diseases © 2011 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd
International Journal of Rheumatic Diseases
Volume 15, Issue 1, pages 36–44, February 2012
How to Cite
MIMATA, Y., KAMATAKI, A., OIKAWA, S., MURAKAMI, K., UZUKI, M., SHIMAMURA, T. and SAWAI, T. (2012), Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritis. International Journal of Rheumatic Diseases, 15: 36–44. doi: 10.1111/j.1756-185X.2011.01656.x
- Issue published online: 13 FEB 2012
- Article first published online: 14 SEP 2011
- fibroblast-like synoviocytes;
- rheumatoid arthritis
Aim: A disintegrin-like and metalloproteinase with thrombospondin type 1 motif (ADAMTS)-4 and ADAMTS-5 play crucial roles in the cleavage of aggrecan. Several recent studies have demonstrated the effect of cytokines such as interleukin (IL)-1β, tumor necrosis factor-α and transforming growth factor-β on the expression of ADAMTS-4 and ADAMTS-5 in fibroblast-like synoviocytes (FLS). However, the effect of IL-6 remains unclear. The aim of this study is to investigate the expression of ADAMTS-4 and ADAMTS-5 in FLS of rheumatoid arthritis (RA) patients after IL-6 stimulation.
Method: Immunohistochemical staining was performed to examine the expression and localization of ADAMTS-4 and ADAMTS-5 in RA synovium. FLS isolated from RA patients were stimulated by IL-6 and soluble IL-6 receptor (sIL-6R) in the presence or absence of anti-IL-6R antibody, and the expression levels of ADAMTS-4 and ADAMTS-5 messenger RNA (mRNA) were assessed using real-time polymerase chain reaction. Furthermore, the IL-6 signaling pathway for regulation of ADAMTS-4 and ADAMTS-5 was also examined.
Results: Staining for ADAMTS-4 and ADAMTS-5 was mainly observed in the sublining layer of synovial membrane and pannus. The expression of ADAMTS-4 mRNA was increased by IL-6/sIL-6R, whereas that of ADAMTS-5 was decreased. Anti-IL-6R antibody suppressed the effect of IL-6/sIL-6R. Mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) kinase (MEK)1/2 inhibitor U0126 inhibited the effect of IL-6/sIL-6R on ADAMTS-4 mRNA expression in FLS. Signal transducer and activator of transcription 3 (STAT3) inhibitor parthenolide inhibited the effect of IL-6/sIL-6R on ADAMTS-4, and downregulated ADAMTS-5 expression.
Conclusion: These results suggest IL-6 may participate in cartilage destruction in RA as an inducer of ADAMTS-4 expression from FLS.