Abstract
BackgroundPatients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro.MethodsSerum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed.ResultsIL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients’ PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of TRAP, NFATC1, CTSK, and TNFRSF11A (RANK) genes were lower in the IL-18BP treated cells.ConclusionWe showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment.
Highlights
Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteo‐ arthritis (OA) or in healthy controls
In a mouse model of RA, the Type 17 helper T cell (Th17)/Regulatory T cell (Treg) imbalance was associated with arthritis progression [2], which implies that Th17/Treg imbalance could be a marker of RA progression
The serum levels of IL-18 and IL-18BP significantly correlated in the active RA subgroup (Rho = 0.705, P < 0.05), whereas no correlation was observed in the inactive RA subgroup (Fig. 1c)
Summary
Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteo‐ arthritis (OA) or in healthy controls. Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that affects approximately 0.5–1% of the general population, and chronic inflammation associated with RA induces irreversible joint destruction, especially. The pathogenesis of RA is complex and dependent on the interactions of various immune cells, osteoclasts, chondrocytes, and synovial lining cells [1], the main pathological immune cause of RA is thought to be a dysregulated adaptive immune reaction. In RA synovium, the CD4+ T cell population producing interleukin (IL)-17 is increased [3]. In a mouse model of RA, the Th17/Treg imbalance was associated with arthritis progression [2], which implies that Th17/Treg imbalance could be a marker of RA progression
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