Effectiveness of the soluble form of the interleukin‐1 receptor accessory protein as an inhibitor of interleukin‐1 in collagen‐induced arthritis

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Abstract
Objective To investigate whether the soluble form of interleukin‐1 (IL‐1) receptor accessory protein (sIL‐1RAcP), whose physiologic function remains to be established, can serve as a specific inhibitor of IL‐1 signaling in vitro, and to evaluate its applicability in collagen‐induced arthritis (CIA). Methods Soluble IL‐1RAcP was cloned from murine liver complementary DNA and expressed by the use of either an adenoviral vector (AdRGD) for sIL‐1RAcP or a stable‐transfected NIH3T3 fibroblast cell line. The ability of affinity‐purified sIL‐1RAcP to inhibit IL‐1 signaling was tested on NF‐κB luciferase reporter fibroblasts and quantified by luminometer. To investigate therapeutic efficacy, sIL‐1RAcP was both locally (knee joint) and systemically overexpressed in collagen‐immunized male DBA/1 mice. Severity of arthritis was monitored visually, and the pathologic process in the joint was examined histologically. Serum was obtained from mice to quantify IL‐6 and anti–bovine type II collagen (BCII) antibody levels. Results Incubation of the NF‐κB reporter fibroblast with purified sIL‐1RAcP protein showed a marked reduction of IL‐1–induced, but not tumor necrosis factor–induced, NF‐κB activation. This showed a novel role for sIL‐1RAcP as a specific inhibitor of IL‐1 signaling. Local transplantation of sIL‐1RAcP–producing NIH3T3 fibroblasts into the knee before onset of CIA had little or no effect on general disease severity in these mice. Histologic evaluation of the knee joints receiving sIL‐1RAcP cell transplantation showed a marked reduction in both joint inflammation and bone and cartilage erosion. Local treatment with sIL‐1RAcP had no profound effect on serum levels of IL‐6 and anti‐BCII antibodies, which is indicative of the ongoing presence of arthritis in distal joints. In contrast to local treatment, systemic treatment with the AdRGD for sIL‐1RAcP markedly ameliorated CIA in all joints. Conclusion In this study we demonstrated that sIL‐1RAcP is a biologically active and innovative inhibitor of IL‐1, and treatment of mice with sIL‐1RAcP had a profound prophylactic effect on collagen‐induced arthritis.
Funding Information
  • European Community (QLRT 1999-02072)
  • Dutch Arthritis Association (99-2-403)
  • National Institutes of Health (R01-HL-67962)
  • United States Department of Defense (P50-CA89019)

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