Mice transgenic for intracellular interleukin-1 receptor antagonist type 1 are protected from collagen-induced arthritis.
Interleukin-1 receptor antagonist (IL-1Ra) is a natural IL-1 inhibitor, which competitively inhibits binding of IL-1 to its receptors. IL-1Ra is produced as four different isoforms, one secreted (sIL-1Ra) and three intracellular (icIL-1Ra1, 2, 3), derived from the same gene. We previously observed increased production of icIL-1Ra1 in the joints of mice with collagen-induced arthritis (CIA). However, due to its intracellular localization, the biological role of icIL-1Ra1 remains unknown. The aim of the present study was to examine the effect of the icIL-1Ra1 isoform, as compared to that of sIL-1Ra, in the CIA model by comparing transgenic (tg) mice overexpressing icIL-1Ra1 or sIL-1Ra to their wild-type littermates. Serum levels of tg human IL-1Ra were elevated in sIL-1Ra and, to a lesser extent, also in icIL-1Ra1 mice. Clinical scoring indicated that none of the icIL-1Ra1 or siL-1Ra tg mice developed CIA, whereas arthritis was present in, respectively, 60% and 100% of their wild-type littermates. Histological and radiological analyses confirmed the absence of arthritis in icIL-1Ra1 and sIL-1Ra tg mice. Accordingly, circulating levels of the acute-phase protein serum amyloid A tended to be lower in icIL-1Ra1 tg mice than in their wild-type littermates and were significantly lower in sIL-1Ra tg mice than in controls. In contrast, no difference was observed between the groups regarding serum levels of anti-type II collagen antibodies and ex vivo spleen cell proliferative response to collagen. In conclusion, icIL-1Ra1, which is released into the extracellular space when produced in high amounts, has a similar anti-arthritic effect as sIL-1Ra.
Palmer
Gaby
G
Division of Rheumatology, University Hospital, Geneva, Switzerland.
Talabot-Ayer
Dominique
D
Szalay-Quinodoz
Ildiko
I
Maret
Michel
M
Arend
William P
WP
Gabay
Cem
C
D018829:Adhesins, Bacterial / Q000097:blood; D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D003433:Crosses, Genetic; D029968:Escherichia coli Proteins / Q000097:blood; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000097:blood / Q000235:genetics / Q000502:physiology; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000502:physiology; D012720:Severity of Illness Index; D012795:Sialoglycoproteins / Q000097:blood / Q000235:genetics / Q000502:physiology*
D018829:Adhesins, Bacterial; D029968:Escherichia coli Proteins; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C439650:SAA protein, E coli; D012795:Sialoglycoproteins