Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis

Richards, Peter James, Nowell, Mari Ann, Horiuchi, Sankichi, McLoughlin, Rachel Mary, Fielding, Ceri Alan ORCID: https://orcid.org/0000-0002-5817-3153, Grau, Sandra, Yamamoto, Naoki, Ehrmann, Michael ORCID: https://orcid.org/0000-0002-1927-260X, Rose-John, Stefan, Williams, Anwen Sian ORCID: https://orcid.org/0000-0001-6118-020X, Topley, Nicholas and Jones, Simon Arnett ORCID: https://orcid.org/0000-0001-7297-9711 2006. Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis. Arthritis & Rheumatism 54 (5) , pp. 1662-1672. 10.1002/art.21818

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Abstract

Objective Soluble gp130 is the naturally occurring antagonist of the interleukin-6 (IL-6)/soluble IL-6 receptor (sIL-6R) complex and selectively inhibits IL-6 trans-signaling. Several isoforms of soluble gp130 have been identified, including an autoantigenic form termed gp130-RAPS (for gp130 of the rheumatoid arthritis antigenic peptide-bearing soluble form) that is present in the serum and synovial fluid of patients with rheumatoid arthritis. The aim of this study was to evaluate the functional properties of gp130-RAPS. Methods To define a role for gp130-RAPS in arthritis, a recombinant version was generated using a baculovirus expression system, and its activities were tested in vitro and in vivo. Results Gp130-RAPS was shown to bind with high affinity to the stable IL-6/sIL-6R complex, hyper-IL-6, and to effectively modulate leukocyte migration in murine acute peritonitis. A single intraarticular injection of gp130-RAPS suppressed chronic antigen-induced arthritis in association with a reduction in local activation of signal transducer and activator of transcription 3. Although gp130-RAPS contains the previously identified autoantigenic sequence Asn-Ile-Ala-Ser-Phe (NIASF), no increase in the prevalence of anti- gp130-RAPS antibodies was observed in serum or synovial fluid obtained from patients with rheumatoid arthritis. Conclusion The use of inhibitory antibodies to block IL-6 responses has shown considerable clinical promise. However, the results presented herein suggest that selective targeting of IL-6 trans-signaling may represent a viable alternative to this strategy. In this respect, our present results suggest that the soluble gp130 isoform gp130-RAPS may be useful in the treatment of chronic inflammatory arthritis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	John Wiley & Sons
ISSN:	0004-3591
Last Modified:	06 Nov 2024 22:35
URI:	https://orca.cardiff.ac.uk/id/eprint/296

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