The natural soluble form of IL-18 receptor beta exacerbates collagen-induced arthritis via modulation of T-cell immune responses.
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.
Veenbergen
S
S
Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Smeets
R L
RL
Bennink
M B
MB
Arntz
O J
OJ
Joosten
L A B
LA
van den Berg
W B
WB
van de Loo
F A J
FA
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
D017252:CD3 Complex; D016207:Cytokines; D020382:Interleukin-18; D053724:Receptors, Interleukin-18; D007371:Interferon-gamma