Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized byinflammation and joint destruction. Migration of monocytes/macrophages into the synovium is important in a variety of vasculoproliferatine states in RA. A disintegrin and metalloprotease (ADAM) are a family of proteases that are responsible for the liberation of a variety of types of cell surface expressed proteins.ADAM-17 has been shown to cleave a number of inflammatory mediators from the cell surface including CX3CL1 and CXCL16. In this study, we examined the expression of ADAM-17 in RA and the role it plays ininflammation.
Methods: ADAM-17 expression was determined in serumand synovial fluids from normal (NL) subjects, osteoarthritis (OA) patients and RA patients using enzyme linked immunosorbent assay. We also measured ADAM-17 in RA serum after treatment with tocilizmab (6, 12 and 24 week). To determine whether ADAM17 was expressed by THP-1 cells (human acute monocytic leukemia cell line)and whether it was regulated byphorbol 12-myristate 13-acetate (PMA), quantitative polymerase chain reaction (qPCR) was performed. In order to confirm the role of ADAM-17 in inflammation, we did THP-1 chemotaxis assay. To block the expression of ADAM-17, THP-1cells were transfected with siRNA against ADAM-17. After treatment with ADAM-17 siRNA, THP-1cell chemotaxis assay wasperformed towards RA synovial fluids and monocyte chemotactic protein-1 (MCP-1)/CCL2.
Results: ADAM-17 in RA serum (n=23) was significantly higher than NL serum (n=7) (mean ± SEM RA serum 2093 ± 538 pg/ml and NL serum 0 ± 0pg/ml). ADAM-17 in RA synovial fluids (n=10) was also significantly higher than OA synovial fluids (n=7) (mean ± SEM RA synovial fluids 1645 ± 952 pg/ml and OA synovial fluids 5±4 pg/ml). After treatment with tocilizmab, ADAM-17 in serum was significantly decreased [pre 486 ± 126pg/ml (n=21), 12 week 215 ± 114 (n=15) and 24 week 98 ± 98 (n=12); p<0.05 between pre and 12 week, pre and 24 week]. The expression of ADAM-17 messenger RNA (mRNA) in THP-1 cells was induced by stimulation withPMA after 1 hour (2.6 fold increased). ADAM-17 siRNA treated THP-1 cells had decreased migration compared with control siRNA treated THP-1 cells towards RA synovial fluids (6± 2number of cells migrated and 33 ± 12 number of cells migrated, p<0.05). ADAM-17 siRNA treated THP-1 cells had also decreased migration compared with control siRNA treated THP-1 cells towards MCP-1/CCL2 (27 ± 4 number of cells migrated and 146 ± 18 number of cells migrated, p<0.05).
Conclusion: These data show that ADAM-17 is overexpressed in RA, and is decreased after treatment.ADAM-17 is involved monocyte migration, and this study suggests that ADAM-17 may play a role in RA inflammation. ADAM-17 may be a potential target in inflammatory disease like RA.
Disclosure:
T. Isozaki,
None;
N. Oguro,
None;
S. Seki,
None;
Y. Miura,
None;
S. Ishii,
None;
H. Tsukamoto,
None;
T. Tokunaga,
None;
M. Umemura,
None;
H. Furuya,
None;
R. Yanai,
None;
S. Isojima,
None;
K. Wakabayashi,
None;
N. Yajima,
None;
Y. Miwa,
None;
T. Kasama,
None.
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