Richards, P.J.; Nowell, Mari A.; Horiuchi, Sankichi; McLoughlin, Rachel M.; Fielding, Ceri A.; Grau, Sandra; Yamamoto, Naoki; Ehrmann, Michael; Rose-John, Stefan; Williams, Anwen S.; Topley, Nicholas; Jones, Simon A.:
Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis
2006
In: Arthritis & rheumatism : an official journal of the American College of Rheumatology, Jg. 54 (2006), Heft 5, S. 1662 - 1672
Artikel/Aufsatz in Zeitschrift2006Biologie
Fakultät für Biologie
Titel:
Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis
Autor(in):
Richards, P.J.; Nowell, Mari A.; Horiuchi, Sankichi; McLoughlin, Rachel M.; Fielding, Ceri A.; Grau, Sandra; Yamamoto, Naoki; Ehrmann, MichaelLSF; Rose-John, Stefan; Williams, Anwen S.; Topley, Nicholas; Jones, Simon A.
Erscheinungsjahr
2006
WWW URL

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.