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Identification of a natural soluble form of the IL-18 receptor accessory protein as an immunomodulator in experimental arthritis


In the inflammatory process preceding erosive arthritis, IL-18 plays an important role. IL-18 is known to regulate immune responses by stimulating Th1 maturation, and signaling is initiated through formation of a trimeric receptor complex, consisting out of IL-18 bound to the IL-18Rα and its accessory receptor IL-18Rβ.


The aim of this study was to determine the physiological role of a recently described soluble form of the IL-18 receptor accessory protein (sIL-18Rβ) in mice.


Mouse sIL-18Rβ (genebank accession number AK053176) was cloned from murine lung cDNA and used for the generation of an adenoviral vector (Ad.5IL-18Rβ). Expression analysis of the sIL-18Rβ and its full-length membrane bound IL-18Rβ in different murine tissue was achieved through endpoint PCR. To investigate the in vivo mode of action, sIL-18Rβ was systemically overexpressed in collagen type II-immunized male DBA/1 mice. Systemical overexpression was achieved through intravenous injection of 3 × 108 pfu Ad5sIL-18Rβ or the control vector (Ad5Luc) before clinical manifestation of collagen-induced arthritis (CIA). At 1 and 4 days post adenoviral injection, splenocytes were harvested and the cytokine profile in plasma and splenocyte culture supernatants was determined


Short IL-18Rβ mRNA was highly expressed in tissue of lymphoid origin, and no expression could be observed in immune privileged organs like the testis, the eye and the brain, suggesting a prominent role in immune regulation. Expression of sIL-18Rβ was disease regulated in mice suffering from CIA, whereas the full-length IL-18Rβ was not regulated. Splenocytes of sIL-18Rβ-treated immunized mice produced significantly less interferon gamma and IL-10 compared with control treated animals. Adenoviral overexpression of the sIL-18Rβ before clinical manifestation of CIA significantly aggravated arthritis, which was accompanied by a reduction of circulating IL-10, interferon gamma and a significant increased anti-bovine collagen II IgG1.


Our results describe the existence of a novel short soluble form of the membrane IL-18Rβ, which is mainly expressed in lymphoid tissues. This sIL-18Rβ expression appears regulated during CIA. Furthermore, we show that this novel soluble IL-18Rβ functions as a putative modulator of IL-18 signaling; aggravating CIA, by modulating T-cell immunity.

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Smeets, R., Arntz, O., Bennink, M. et al. Identification of a natural soluble form of the IL-18 receptor accessory protein as an immunomodulator in experimental arthritis. Arthritis Res Ther 7 (Suppl 1), P89 (2005).

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