Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production.
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-1beta-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-6Ralpha mRNA ratio increased by approximately 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.
Ahmed
Salahuddin
S
Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Marotte
Hubert
H
Kwan
Kevin
K
Ruth
Jeffrey H
JH
Campbell
Phillip L
PL
Rabquer
Bradley J
BJ
Pakozdi
Angela
A
Koch
Alisa E
AE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130; D002392:Catechin; C045651:epigallocatechin gallate; D020778:Matrix Metalloproteinase 2
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