Objective: Interleukin-18 (IL-18) is a pluripotent cytokine that has been implicated in the development of rheumatoid arthritis (RA). Recently, a soluble form of the IL-18Receptor accessory protein (sIL-18Rβ) with unknown function has been identified. In this study, we examined the ability of sIL-18Rβ to inhibit IL-18 biological activities and modulate immune responses during collagen-induced arthritis (CIA).
Methods: Adenoviruses encoding sIL-18Rβ were administered intravenously in type II collagen-immunized DBA/1 mice. Humoral responses were analyzed by determining anti-bovine type II collagen antibody levels (anti-BCII) 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-18Rβ in collagen-immunized mice led to enhanced transgene expression in splenic APCs. A co-culture of these sIL-18Rβ-transduced APCs with purified splenic CD3+ T cells led to a marked inhibition of IL-18-induced IFNγ, IL-4 and IL-17 production by CD3+ T cells. Remarkably, systemic treatment with Ad5.sIL-18Rβ 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 IFNγ (-30%) and IL-4 (-44%), and increased IL-17 (+84%) production by splenic CD3+ T cells. Additionally, reduced circulating levels of CD4+CD25+Foxp3+ Treg and anti-inflammatory IL-10 was shown.
Conclusion: This study identifies sIL-18Rβ as a novel IL-18 inhibitor, that promotes CIA after intravenous overexpression by affecting Treg levels and supporting a Th17 response.