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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (38), p.14692-14697
• Main Authors: Ahmed, Salahuddin, Marotte, Hubert, Kwan, Kevin, Ruth, Jeffrey H, Campbell, Phillip L, Rabquer, Bradley J, Pakozdi, Angela, Koch, Alisa E
• Format: Article
• Language: English
• Subjects: Alternative splicing; Animals; anti-inflammatory activity; Anti-Inflammatory Agents - pharmacology; Arthritis; Arthritis, Rheumatoid - drug therapy; Biological Sciences; Catechin - analogs & derivatives; Catechin - pharmacology; Cells, Cultured; Cytokine Receptor gp130 - biosynthesis; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Cytokines; Cytokines - blood; Disease Models, Animal; enzyme activity; epigallocatechin-3-gallate; Female; Fibroblasts; Fibroblasts - drug effects; flavanols; Gene Expression Regulation - drug effects; Genes; glycoprotein gp130; green tea; Green teas; Humans; Inflammation; interleukin-1; Interleukin-1beta - metabolism; interleukin-6; Interleukin-6 - biosynthesis; Interleukin-6 - blood; Interleukin-6 - genetics; Interleukin-6 - metabolism; Joints; Matrix Metalloproteinase 2 - metabolism; membrane proteins; Messenger RNA; metalloproteinases; Protein synthesis; Rats; Rats, Inbred Lew; Receptors; Receptors, Interleukin-6 - metabolism; Rheumatoid arthritis; Rodents; signal transduction; Synovial Membrane - cytology; therapeutics; Up-Regulation - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0802675105

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-1β-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-6Rα mRNA ratio increased by ~2-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.