title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Cardiff University, Cardiff, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Richards
authors.forename: Mari A
authors.initials: MA
authors.lastname: Nowell
authors.forename: Sankichi
authors.initials: S
authors.lastname: Horiuchi
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
authors.forename: Ceri A
authors.initials: CA
authors.lastname: Fielding
authors.forename: Sandra
authors.initials: S
authors.lastname: Grau
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000276:immunology; D050822:Cytokine Receptor gp130 / Q000302:isolation & purification* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000627:therapeutic use
chemical_list: D020033:Protein Isoforms; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130