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.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.