Journal Article

IL-18 binding protein suppresses IL-17-induced osteoclastogenesis and rectifies type 17 helper T cell / regulatory T cell imbalance in rheumatoid arthritis

Kim, Hae-Rim, Lee, Ji-Yeon, Lee, Sang-Heon, Min, Hong Ki, Kim, Sehee, Kim, Kyoung-Woon

2021

Overview

Background 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 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. Methods Serum 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. Results IL-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 + CD25 high FOXP3 + 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. Conclusion We 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acid phosphatase (tartrate-resistant) / Arthritis, Rheumatoid / Binding proteins / Biomedical and Life Sciences / Biomedicine / CD25 antigen / CD4 antigen / Cell culture / Cell differentiation / Cells, Cultured / Cytokines / Development and progression / Disease / Drug therapy / Enzyme-linked immunosorbent assay / Gene expression / Health aspects / Helper cells / Humans / Immunobiology and immunotherapy / Inflammation / Intercellular Signaling Peptides and Proteins / Interleukin 17 / Interleukin 18 / Interleukin-18 binding protein / Leukocytes, Mononuclear / Lymphocytes / Lymphocytes T / Medicine/Public Health / Monoclonal antibodies / Osteoarthritis / Osteoclastogenesis / Osteoclasts / Osteoclasts (Biology) / Osteogenesis / Osteoprotegerin / Pathogenesis / Patients / Peripheral blood mononuclear cells / Physiological aspects / Polymerase chain reaction / Proteins / RANK Ligand / Regulatory T cell / Rheumatoid arthritis / Synovial fluid / T-Lymphocytes, Regulatory / Th17 Cells / TRANCE protein / Type 17 helper T cell