Effectiveness of the soluble form of the interleukin-1 receptor accessory protein as an inhibitor of interleukin-1 in collagen-induced arthritis.
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-kappaB 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-kappaB reporter fibroblast with purified sIL-1RAcP protein showed a marked reduction of IL-1-induced, but not tumor necrosis factor-induced, NF-kappaB 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.


CONCLUSIONS
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.
Smeets
R L
RL
University Medical Center Nijmegen, Nijmegen, The Netherlands.
van de Loo
F A J
FA
Joosten
L A B
LA
Arntz
O J
OJ
Bennink
M B
MB
Loesberg
W A
WA
Dmitriev
I P
IP
Curiel
D T
DT
Martin
M U
MU
van den Berg
W B
WB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D003001:Cloning, Molecular; D015870:Gene Expression; D015316:Genetic Therapy; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein; D007719:Knee Joint / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells / Q000502:physiology / Q000637:transplantation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility
C507767:Il1rap protein, mouse; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D016328:NF-kappa B; D011506:Proteins