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The natural soluble form of il-18 receptor β exacerbates collagen-induced arthritis via modulation of t cell immune responses
  1. Sharon Veenbergen (sveenbergen{at}reuma.umcn.nl)
  1. Radboud University Nijmegen Medical Centre, Netherlands
    1. Ruben L Smeets (ruben.smeets{at}spcorp.com)
    1. Radboud University Nijmegen Medical Centre, Netherlands
      1. Miranda B Bennink (m.bennink{at}reuma.umcn.nl)
      1. Radboud University Nijmegen Medical Centre, Netherlands
        1. Onno J Arntz (a.arntz{at}reuma.umcn.nl)
        1. Radboud University Nijmegen Medical Centre, Netherlands
          1. Leo AB Joosten (l.joosten{at}aig.umcn.nl)
          1. Radboud University Nijmegen Medical Centre, Netherlands
            1. Wim B van den Berg (w.vandenberg{at}reuma.umcn.nl)
            1. Radboud University Nijmegen Medical Centre, Netherlands
              1. Fons AJ van de Loo (a.vandeloo{at}reuma.umcn.nl)
              1. Radboud University Nijmegen Medical Centre, Netherlands

                Abstract

                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.

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