Mice transgenic for intracellular interleukin‐1 receptor antagonist type 1 are protected from collagen‐induced arthritis

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Abstract
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.