Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Abstract

Objective. To discern the mode of interleukin-1 (IL-1) inhibition of soluble IL-1 receptor accessory protein (sIL-1RAcP) by comparison with IL-1 receptor antagonist (IL-1Ra) in arthritis.Methods. Adenoviral vectors encoding either sIL1RAcP or IL-1Ra were administered systemically before onset of collagen-induced arthritis in DBA/1 mice. Antibovine type II collagen IgG and IL-6 were quantified in serum. Proliferative response of splenic T cells was determined in the presence of sIL-1RAcP or IL-1Ra. The effect on IL-1 inhibition of recombinant sIL-1RAcP and IL-1Ra was further examined in vitro, using NF-B luciferase reporter cell lines. Quantitative polymerase chain reaction was used to determine the relative messenger RNA expression of the IL-1 receptors.Results. Adenoviral overexpression of both sIL1RAcP and IL-1Ra resulted in amelioration of the collagen-induced arthritis. Both IL-1 antagonists reduced the circulating levels of antigen-specific IgG2a antibodies, but only IL-1Ra was able to inhibit lymphocyte proliferation. By using purified lymphocyte populations derived from NF-B reporter mice, we showed that sIL-1RAcP inhibits IL-1-induced NF-B activity in B cells but not T cells, whereas IL-1Ra inhibited IL-1 on both cell types. A study in a panel of NF-B luciferase reporter cells showed that the sIL-1RAcP inhibits IL-1 signaling on cells expressing either low levels of membrane IL-1RAcP or high levels of IL-1RII.Conclusion. We show that the sIL-1RAcP ameliorated experimental arthritis without affecting T cell immunity, in contrast to IL-1Ra. Our results provide data in support of receptor competition by sIL-1RAcP as an explanation for the different mode of IL-1 antagonism in comparison with IL-1Ra.

The many worlds of reducing interleukin‐1

“…In a report in this issue of Arthritis & Rheumatism, Smeets et al (20) show that there is a selective effect on lymphocyte activation when 2 different methods for blocking IL-1 are compared in the mouse model of collagen-induced arthritis (CIA). They compared overexpression of IL-1Ra with overexpression of the soluble form of the IL-1 coreceptor, termed the IL-1 receptor accessory protein (sIL-1RAcP).…”

Enhancement of Adenovirus-Mediated Gene Delivery to Rheumatoid Arthritis Synoviocytes and Synovium by Fiber Modifications: Role of Arginine-Glycine-Aspartic Acid (RGD)- and Non-RGD-Binding Integrins

“…CIA was induced in male (8 -10 wk old) DBA1 mice (Bomholtgard Breeding and Research Center) with bovine type II collagen (bCII) as described previously (40). All in vivo studies complied with national legislation and were approved by local authorities of the Care of Use of Animals with related codes of practice.…”

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

“…2B) and IL-33-IL-1RL1 complexes with the membrane-bound IL-1RAP required for signaling (50,(56)(57)(58) and (ii) enhancing the affinities of IL-1R2 for IL-1a and IL-1b (Fig. 2B) and sIL-1RL1 for IL-33 ( Fig.…”