Cloning of novel soluble gp130 and detection of its neutralizing autoantibodies in rheumatoid arthritis

Tanaka, Masao; Kishimura, Masaaki; Ozaki, Shoichi; Osakada, Fumio; Hashimoto, H; Okubo, Mitsuo; Murakami, Masao; Nakao, Kazuwa

doi:10.1172/jci7479

Cited by 64 publications

(49 citation statements)

References 26 publications

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“…Significantly, several isoforms of sgp130 have been described (21). However, one form known as gp130-RAPS (RA antigenic peptide-bearing soluble form) has recently been identified as an RA autoantigen, and serum Abs against gp130-RAPS not only correlate with indices of disease activity, but also neutralize gp130-RAPS activity (52). Although the significance of these findings needs to be clarified, sgp130 may symbolize a valuable addition to the current arsenal of therapeutics that have proven so effective in the management of chronic conditions such as RA.…”

Section: Discussionmentioning

confidence: 99%

Soluble IL-6 Receptor Governs IL-6 Activity in Experimental Arthritis: Blockade of Arthritis Severity by Soluble Glycoprotein 130

Nowell

Richards

Horiuchi

et al. 2003

The Journal of Immunology

233

224

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Studies in IL-6-deficient (IL-6−/−) mice highlight that IL-6 contributes to arthritis progression. However, the molecular mechanism controlling its activity in vivo remains unclear. Using an experimental arthritis model in IL-6−/− mice, we have established a critical role for the soluble IL-6R in joint inflammation. Although intra-articular administration of IL-6 itself was insufficient to reconstitute arthritis within these mice, a soluble IL-6R-IL-6 fusion protein (HYPER-IL-6) restored disease activity. Histopathological assessment of joint sections demonstrated that HYPER-IL-6 increased arthritis severity and controlled intrasynovial mononuclear leukocyte recruitment through the CC-chemokine CCL2. Activation of synovial fibroblasts by soluble IL-6R and IL-6 emphasized that these cells may represent the source of CCL2 in vivo. Specific blockade of soluble IL-6R signaling in wild-type mice using soluble gp130 ameliorated disease. Consequently, soluble IL-6R-mediated signaling represents a promising therapeutic target for the treatment of rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 99%

Soluble IL-6 Receptor Governs IL-6 Activity in Experimental Arthritis: Blockade of Arthritis Severity by Soluble Glycoprotein 130

Nowell

Richards

Horiuchi

et al. 2003

The Journal of Immunology

233

224

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“…S2). Amplification of gp130 mRNA using full-length mgp130, alternatively spliced sgp130, and gp130-RAPS mRNA transcripts was performed by qualitative RT-PCR (qRT-PCR) (20,21). The results showed that EGCG inhibited gp130 mRNA encoding full-length gp130 but enhanced sgp130 and gp130-RAPS mRNA when used alone or in the presence of IL-1␤ (Fig.…”

Section: Egcgmentioning

confidence: 96%

Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production

Ahmed

Marotte

Kwan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

121

134

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Regulation of IL-6 transsignaling by the administration of soluble gp130 (sgp130) receptor to capture the IL-6/soluble IL-6R complex has shown promise for the treatment of rheumatoid arthritis (RA). However, enhancing endogenous sgp130 via alternative splicing of the gp130 gene has not yet been tested. We found that epigallocatechin-3-gallate (EGCG), an anti-inflammatory compound found in green tea, inhibits IL-1␤-induced IL-6 production and transsignaling in RA synovial fibroblasts by inducing alternative splicing of gp130 mRNA, resulting in enhanced sgp130 production. Results from in vivo studies using a rat adjuvant-induced arthritis model showed specific inhibition of IL-6 levels in the serum and joints of EGCG-treated rats by 28% and 40%, respectively, with concomitant amelioration of rat adjuvant-induced arthritis. We also observed a marked decrease in membrane-bound gp130 protein expression in the joint homogenates of the EGCG-treated group. In contrast, quantitative RT-PCR showed that the gp130/IL-6R␣ mRNA ratio increased by ϳ2-fold, suggesting a possible mechanism of sgp130 activation by EGCG. Gelatin zymography results showed EGCG inhibits IL-6/soluble IL-6R-induced matrix metalloproteinase-2 activity in RA synovial fibroblasts and in joint homogenates, possibly via up-regulation of sgp130 synthesis. The results of these studies provide previously undescribed evidence of IL-6 synthesis and transsignaling inhibition by EGCG with a unique mechanism of sgp130 up-regulation, and thus hold promise as a potential therapeutic agent for RA.rheumatoid arthritis ͉ alternative splicing ͉ cytokine therapy ͉ pharmacology ͉ therapeutics

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“…Three soluble isoforms of gp130 have previously been found in human serum and urine, with apparent molecular masses of about 50, 90, and 110 kDa, respectively. So far, only the 50-kDa isoform sgp130-RAPS was assigned to a differentially spliced mRNA (5,7,8).…”

Section: Discussionmentioning

confidence: 99%

“…At least three soluble gp130 receptor isoforms of ϳ110, 90, and 50 kDa have been detected in serum or urine (4 -6). Only the protein corresponding to the differentially spliced mRNA of the smallest (50 kDa) isoform sgp130-RAPS was verified by Western blotting using specific antibodies directed against the novel C terminus of sgp130-RAPS (5,7,8). Two additional differentially spliced gp130 cDNAs were described, but have not been shown to be endogenously translated into sgp130 proteins (7,8).…”

mentioning

confidence: 99%

Alternative Intronic Polyadenylation Generates the Interleukin-6 Trans-signaling Inhibitor sgp130-E10

Sommer

Garbers²,

Wolf³

et al. 2014

Journal of Biological Chemistry

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Background: Interleukin (IL)-6 trans-signaling is inhibited by naturally occurring soluble gp130 (sgp130) variants. Results: Alternative intronic polyadenylation in the gp130 gene creates the novel natural IL-6 trans-signaling inhibitor sgp130-E10. Conclusion: Alternative mRNA polyadenylation contributes to regulation of IL-6 trans-signaling intensity. Significance: This is the first report on a soluble isoform of the key cytokine co-receptor gp130 originating from alternative polyadenylation.

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Cloning of novel soluble gp130 and detection of its neutralizing autoantibodies in rheumatoid arthritis

Cited by 64 publications

References 26 publications

Soluble IL-6 Receptor Governs IL-6 Activity in Experimental Arthritis: Blockade of Arthritis Severity by Soluble Glycoprotein 130

Soluble IL-6 Receptor Governs IL-6 Activity in Experimental Arthritis: Blockade of Arthritis Severity by Soluble Glycoprotein 130

Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production

Alternative Intronic Polyadenylation Generates the Interleukin-6 Trans-signaling Inhibitor sgp130-E10

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