The natural soluble form of IL-18 receptor beta exacerbates collagen-induced arthritis via modulation of T-cell immune responses

Objective: IL-18 is a pluripotent cytokine that has been implicated in the development of rheumatoid arthritis. A soluble form of the IL-18 receptor accessory protein (sIL-18R beta) with unknown function has recently been identified. This study examined the ability of sIL-18R beta to inhibit IL-18 biological activities and to modulate immune responses during collagen-induced arthritis (CIA). Methods: Adenoviruses encoding sIL-18R beta were administered intravenously in type II collagen-immunised DBA/1 mice. Humoral responses were analysed by determining anti-bovine collagen type II (BCII) antibody levels by ELISA. Cytokine production by splenic T cells and cytokine levels in serum were measured by Luminex multi-analyte technology. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) were measured by flow cytometry. Results: Intravenous delivery of Ad5. sIL-18R beta in collagen-immunised mice led to enhanced transgene expression in splenic antigen-presenting cells (APC). A coculture of these sIL-18R beta-transduced APC with purified splenic CD3(+) T cells led to a marked inhibition of IL-18-induced IFN gamma, IL-4 and IL-17 production by CD3(+) T cells. Remarkably, systemic treatment with Ad5. sIL-18R beta caused an exacerbation of arthritis, and histological evaluation of knee joints showed increased cartilage and bone erosion. No significant differences were observed in anti-BCII antibodies, but the aggravation was accompanied by decreased IFN gamma (-30%) and IL-4 (-44%) and increased IL-17 (+84%) production by splenic CD3(+) T cells. In addition, reduced circulating levels of CD4(+)CD25(+)Foxp3(+) Treg and anti-inflammatory IL-10 were shown. Conclusion: This study identifies sIL-18R beta as a novel IL-18 inhibitor, which promotes CIA after intravenous overexpression by affecting Treg levels and supporting a T helper type 17 response.