Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
FMS-Like Tyrosine Kinase 3 Receptor Inhibition Leads to Decreased Production of Interleukin 6 by Synovial Biopsies, Fibroblast-Like Synoviocytes and Monocytic Cells From Arthritic Patients.
Ramos, Maria I. Martins, Aarrass, Saïda, Gerlag, Danielle M., Tak, PP., Lebre, Maria C.
Rheumatoid arthritis (RA) is characterized by inflammation of the synovial membrane and synovial lining hyperplasia, which results in erosion of cartilage and bone. Fibroblast-like synoviocytes (FLS) and macrophages play critical roles in this destructive process by producing inflammatory cytokines. Interleukin 6 (IL-6) is a key inflammatory cytokine in the pathobiology of RA and biological therapies targeting the IL-6 receptor have shown clinical benefit. Fms-like tyrosine kinase 3 ligand (FLT3L) plays a major role in dendritic cell (DC) biology. Flt3L can be detected in RA synovial fluid (SF) and serum and we have shown that Flt3L and its receptor are also expressed in other arthritic diseases. This axis exerts both pro-inflammatory and tissue destructive properties once in the joint cavity. Therefore we examined the effect(s) of a specific Flt3 inhibitor on IL-6 production by synovial biopsies from arthritic patients, cultured FLS and monocytic cells.
Synovial tissue biopsy specimens were obtained by arthroscopy and cultured in the absence or in the presence of a Flt3 specific inhibitor (50100 nM, CEP-701) for 4 days. Monocytes were isolated from peripheral blood mononuclear cells (PBMC) by Ficoll gradient followed by Percoll gradient. Macrophages and DC were generated by culturing monocytes with GM-CSF or GM-CSF+IL-4, respectively. FLS and monocytic cells were cultured in the absence or in the presence of CEP-701 (50100 nM). After 24h (monocytic cells and FLS) or after 4 days (synovial biopsies) IL-6 production was measured by ELISA.
CEP-701 efficiently suppressed spontaneous production of IL-6 by synovial biopsies. As the main producers of IL-6 in the inflamed joint are synovial fibroblasts and macrophages we investigated the production of this inflammatory cytokine by these cells. Indeed, CEP-701 treatment blocked IL-6 levels in both FLS and monocytic cells.
Our findings suggest that therapies targeting Flt3L/Flt3 activity may be useful in suppressing inflammation in RA and other rheumatic diseases
To cite this abstract, please use the following information:
Ramos, Maria I. Martins, Aarrass, Saïda, Gerlag, Danielle M., Tak, PP., Lebre, Maria C.; FMS-Like Tyrosine Kinase 3 Receptor Inhibition Leads to Decreased Production of Interleukin 6 by Synovial Biopsies, Fibroblast-Like Synoviocytes and Monocytic Cells From Arthritic Patients. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1843