Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis.
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.
Richards
Peter J
PJ
Cardiff University, Cardiff, UK.
Nowell
Mari A
MA
Horiuchi
Sankichi
S
McLoughlin
Rachel M
RM
Fielding
Ceri A
CA
Grau
Sandra
S
Yamamoto
Naoki
N
Ehrmann
Michael
M
Rose-John
Stefan
S
Williams
Anwen S
AS
Topley
Nicholas
N
Jones
Simon A
SA
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
D020033:Protein Isoforms; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130