title: The natural soluble form of IL-18 receptor beta exacerbates collagen-induced arthritis via modulation of T-cell immune responses.
abstract: 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-18Rbeta) with unknown function has recently been identified. This study examined the ability of sIL-18Rbeta to inhibit IL-18 biological activities and to modulate immune responses during collagen-induced arthritis (CIA).
  
  
  METHODS
  Adenoviruses encoding sIL-18Rbeta 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-18Rbeta in collagen-immunised mice led to enhanced transgene expression in splenic antigen-presenting cells (APC). A co-culture of these sIL-18Rbeta-transduced APC with purified splenic CD3(+) T cells led to a marked inhibition of IL-18-induced IFNgamma, IL-4 and IL-17 production by CD3(+) T cells. Remarkably, systemic treatment with Ad5.sIL-18Rbeta 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 IFNgamma (-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.
  
  
  CONCLUSIONS
  This study identifies sIL-18Rbeta as a novel IL-18 inhibitor, which promotes CIA after intravenous overexpression by affecting Treg levels and supporting a T helper type 17 response.
authors.affiliation: Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Veenbergen
authors.forename: R L
authors.initials: RL
authors.lastname: Smeets
authors.forename: M B
authors.initials: MB
authors.lastname: Bennink
authors.forename: O J
authors.initials: OJ
authors.lastname: Arntz
authors.forename: L A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: F A J
authors.initials: FA
authors.lastname: van de Loo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D017252:CD3 Complex / Q000032:analysis; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry / Q000379:methods; D005822:Genetic Vectors; D056747:Immunomodulation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D053724:Receptors, Interleukin-18 / Q000276:immunology*; D012995:Solubility; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014162:Transfection
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D020382:Interleukin-18; D053724:Receptors, Interleukin-18; D007371:Interferon-gamma