Richards, Peter 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.:

Baculovirus expression and functional characterization of a recombinant human soluble gp130 isoform and its role in the regulation of IL-6 trans-signaling.

In: Arthritis & rheumatism : an official journal of the American College of Rheumatology, Jg. 54 (2006) ; Nr. 5, S. 1662-1672
ISSN: 0004-3591
Zeitschriftenaufsatz / Fach: Biologie
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 antigeninduced
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.