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

• Published in: Annals of the rheumatic diseases Vol. 69; no. 1; pp. 276 - 283
• Main Authors: Veenbergen, S, Smeets, R L, Bennink, M B, Arntz, O J, Joosten, L A B, van den Berg, W B, van de Loo, F A J
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.01.2010
• Subjects: Adenoviridae - genetics; Animals; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; CD3 Complex - analysis; Cells, Cultured; Cytokines - biosynthesis; Flow Cytometry - methods; Genetic Vectors; Immunomodulation - immunology; Interferon-gamma - biosynthesis; Interleukin-18 - immunology; Male; Mice; Mice, Inbred DBA; Receptors, Interleukin-18 - immunology; Solubility; Spleen - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology; Transfection
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.2008.100867

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.