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 sIL-1RAcP or IL-1Ra were administered systemically before onset of collagen-induced arthritis in DBA/1 mice. Anti-bovine 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-kappaB 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 sIL-1RAcP 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-kappaB reporter mice, we showed that sIL-1RAcP inhibits IL-1-induced NF-kappaB 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-kappaB 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.

• Authors: R L Smeets, L A B Joosten, O J Arntz, M B Bennink, N Takahashi, H Carlsen, M U Martin, W B van den Berg, F A J van de Loo
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 52 Issue 7 Pg. 2202-11 (Jul 2005) ISSN: 0004-3591 [Print] United States
• PMID: 15986350 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Il1rap protein, mouse
• Interleukin-1
• Interleukin-1 Receptor Accessory Protein
• NF-kappa B
• Proteins
• RNA, Messenger
• Receptors, Interleukin-1

Topics

• Adenoviridae (genetics)
• Animals
• Arthritis, Experimental (metabolism, pathology, therapy)
• B-Lymphocytes (immunology, metabolism)
• Cattle
• Cell Proliferation
• Disease Models, Animal
• Gene Expression
• Genetic Therapy
• Interleukin-1 (antagonists & inhibitors, metabolism)
• Interleukin-1 Receptor Accessory Protein
• Male
• Mice
• Mice, Inbred DBA
• NF-kappa B (genetics, metabolism)
• Proteins (genetics, metabolism)
• RNA, Messenger (metabolism)
• Receptors, Interleukin-1 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Spleen (immunology, metabolism)
• T-Lymphocytes (immunology, metabolism)