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
Cardiff University, Cardiff, UK.
Arthritis Rheum. 2006 May;54(5):1662-72. doi: 10.1002/art.21818.
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.
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.
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.
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.
可溶性gp130是白细胞介素-6（IL-6）/可溶性IL-6受体（sIL-6R）复合物的天然拮抗剂，可选择性抑制IL-6转信号传导。已鉴定出可溶性gp130的几种异构体，包括一种自身抗原形式，称为gp130-RAPS（类风湿性关节炎抗原肽携带可溶性形式的gp130），其存在于类风湿性关节炎患者的血清和滑液中。本研究的目的是评估gp130-RAPS的功能特性。
为了确定gp130-RAPS在关节炎中的作用机制，使用杆状病毒表达系统生成了重组体，并在体外和体内测试了其活性。
研究发现，gp130-RAPS与稳定的IL-6/sIL-6R复合物、超IL-6具有高亲和力结合，并能有效调节小鼠急性腹膜炎中的白细胞迁移。单次关节内注射gp130-RAPS可抑制慢性抗原诱导的关节炎，并伴有信号转导和转录激活因子3的局部激活减少。虽然gp130-RAPS包含先前鉴定的自身抗原序列Asn-Ile-Ala-Ser-Phe（NIASF），但在类风湿性关节炎患者的血清或滑液中未观察到抗gp130-RAPS抗体的患病率增加。
使用抑制性抗体阻断IL-6反应已显示出可观的临床前景。然而，本文给出的结果表明，选择性靶向IL-6转信号传导可能是该策略的可行替代方案。在这方面，我们目前的结果表明，可溶性gp130异构体gp130-RAPS可能对慢性炎症性关节炎的治疗有用。
