AB0028 Fibroblast-like synoviocytes may not be the target of il-33 in the joint phisiopathology
Authors: CRL Machado, GG Resende, RBV Macedo, VC Nascimento, TP Silva, AM Kakehasi, MVM Andrade
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic joint diseases in which fibroblast-like synoviocytes (FLS) actively participate in the synovitis- damage cycle, trough production of cytokines such as IL-6 and metalloproteinases (MMPs)<sup>(1)</sup>. It has already been showed that serum IL-33 levels correlated with disease activity in RA<sup>(2)</sup>. IL-33 is capable to enhance TNF-α effects in FLS<sup>(3)</sup>. In the collagen-induced arthritis (CIA) model, the injection of IL-33 exacerbated the disease<sup>(4)</sup>. Since ST2 receptor is expressed in FLS, it is hypothesized that IL-33 could activate FLS and increase downstream production of inflammatory cytokines. <h3>Objectives</h3> To evaluate the production of IL-6, MMP-1, and MMP-3 by FLS stimulated with IL-33, TNF-α, and IL-1β. <h3>Methods</h3> FLS were cultured from samples of synovial fluid and tissue of OA patients (OAFLS n=8), RA patients (RAFLS n=3), and patients without rheumatic disease (health) (HFLS n=4). FLS were stimulate with TNF-α at concentrations of 1; 5; 10 and 50 ng/ml, IL-1β at concentrations of 0.1; 0.2; 0.3; 0.5 and 1 ng/ml and IL-33 at concentrations of 1; 3; 10; 30; 100 ng/ml, soon after, IL-6, MMP-1, and MMP-3 levels were evaluated by ELISA, in the cell supernatant. <h3>Results</h3> MMP-1, MMP-3 and IL-6 were constitutively expressed by FLS at baseline in all groups. Both TNF-α and IL-1β stimulated the production of IL-6 and MMP-1 with statistical significance in a dose-dependent manner in all three groups. Only IL-1β increased the production of MMP-3. TNF-α stimulated the production of MMP-3 only on HFLS. There was no difference between the concentration of MMP-1, MMP-3 and IL6 in the supernatant of OAFLS, ARFLS and HFLS when IL-33 stimulated and non-stimulated were compared. <h3>Conclusions</h3> This study demonstrated that IL-33 failed to induce the production of IL-6, MMP-1 and MMP-3 by FLS of different diseases sources, suggesting that must be another cell type that plays the role of target to IL-33 in physiopathology of joint inflammation. The absence MMP-3 in response to TNF-α stimulus in RAFLS and OAFLS could be explain by saturation of this cytokine in synovial cells from these diseases. <h3>References</h3> Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunological reviews. 2010;233(1):233–55. Matsuyama Y, Okazaki H, Tamemoto H, Kimura H, Kamata Y, Nagatani K, et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. The Journal of rheumatology. 2010;37(1):18–25. Kunisch E, Chakilam S, Gandesiri M, Kinne RW. IL-33 regulates TNF-alpha dependent effects in synovial fibroblasts. International journal of molecular medicine. 2012;29(4):530–40. Xu D, Jiang HR, Kewin P, Li Y, Mu R, Fraser AR, et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(31):10913–8. <h3>Acknowledgements</h3> Capes, Fapemig and Fundo de Apoio a Pesquisa e Ensino da Sociedade Brasileira de Reumatologia - FAPE-SBR. <h3>Disclosure of Interest</h3> None declared