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-18Rβ) with unknown function has recently been identified. This study examined the ability of sIL-18Rβ to inhibit IL-18 biological activities and to modulate immune responses during collagen-induced arthritis (CIA).
Methods: Adenoviruses encoding sIL-18Rβ 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-18Rβ in collagen-immunised mice led to enhanced transgene expression in splenic antigen-presenting cells (APC). A co-culture of these sIL-18Rβ-transduced APC 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. In addition, reduced circulating levels of CD4+CD25+Foxp3+ Treg and anti-inflammatory IL-10 were shown.
Conclusion: This study identifies sIL-18Rβ as a novel IL-18 inhibitor, which promotes CIA after intravenous overexpression by affecting Treg levels and supporting a T helper type 17 response.
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Funding This study was financially supported by the Dutch Arthritis Association (grant no 05-2-301) and Radboud University Nijmegen Medical Centre. FAJvdL is supported by Dutch Organization for Scientific Research (grant no 917.46.363).
Competing interests None.
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