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

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.

• Authors: Peter J Richards, Mari A Nowell, Sankichi Horiuchi, Rachel M McLoughlin, Ceri A Fielding, Sandra Grau, Naoki Yamamoto, Michael Ehrmann, Stefan Rose-John, Anwen S Williams, Nicholas Topley, Simon A Jones
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 54 Issue 5 Pg. 1662-72 (May 2006) ISSN: 0004-3591 [Print] United States
• PMID: 16646038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Isoforms
• Recombinant Proteins
• Cytokine Receptor gp130

Topics

• Animals
• Arthritis (drug therapy, immunology)
• Cytokine Receptor gp130 (isolation & purification, therapeutic use)
• Humans
• Mice
• Mice, Inbred C57BL
• Protein Isoforms
• Recombinant Proteins (isolation & purification, therapeutic use)