Targeting RA Inflammation With Green Tea Compound EGCG

A molecule found in green tea was found to regulate transforming growth factor β–activated kinase 1 (TAK1) in human rheumatoid arthritis synovial fibroblasts (RASF), indicating that TAK1 regulation may be a future therapeutic target in rheumatoid arthritis (RA), according to a study published in Arthritis and Rheumatology.¹

The molecule, a phytochemical called epigallocatechin-3-gallate (EGCG), appears to effectively inhibit TAK1 by blocking its phosphorylation. TAK1 is a mediator of inflammation,  and is integral to the activation of downstream mitogen-activated protein kinases (MAPKs) in response to receptor stimulation by the inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF).

Researchers then analyzed the mechanism of TAK1 regulation in a rat model of adjuvant-induced arthritis (AIA) to see if EGCG could inhibit TAK1 and reduce RA symptom severity.  After 10 days of treatment with EGCG, the researchers found a significant reduction in rat ankle circumference, a measurement that was used as a surrogate for symptomatic inflammation.

Joint homogenates from EGCG-treated rats showed a marked decrease in the expression of pTAK1, total TAK1, and TNF receptor-associated factor 6 (TRAF 6), which are all molecules involved in the modulation of IL-1β–induced signaling (P < 0.05 for pTAK1 [Ser439], total TAK1, and TRAF6).

“This study has opened the field of research into using EGCG for targeting TAK1 – an important signaling protein – through which pro-inflammatory cytokines transmit their signals to cause inflammation and tissue destruction in RA,” said Salah-uddin Ahmed, PhD, from Washington State University College of Pharmacy in Spokane.

Summary and Clinical Applicability

In RA, the overexpression of IL-1β and TNF in the synovium contributes to joint pain, inflammation, and tissue destruction.  In this study, TAK1 regulation was found to modulate IL-1β signaling and decrease signs of inflammation in a rat model of autoimmune arthritis.

While a recombinant human IL-1 receptor (IL-1R) antagonist, anakinra, lacked clinical efficacy in the treatment of RA², this study identified a distinct signaling pathway that could potentially emerge as a therapeutic target in RA, and advance the research necessary to develop unique small-molecule inhibitors of IL-1β.

The authors write, “We have provided a rationale for targeting RASF TAK1 in RA and identified a unique mechanism through which EGCG inhibits the interaction between signaling molecules important in cytokine signaling, ultimately inhibiting inflammation and tissue destruction in RA”.

“This study provides a unique mechanism of therapeutically regulating TRAF6 via reversible inhibition of its function..by EGCG without jeopardizing its physiologic functions… Rationalizing drug design approaches in light of these findings may yield more potent and safer drugs for the treatment of RA and other inflammatory diseases” the authors indicate.

Reference

1.      Singh AK, Umar S, Riegsecker S, et al. Regulation of transforming growth factor β–activated kinase activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts: suppression of K63-linked autoubiquitination of tumor necrosis factor receptor–associated factor 6. Arthritis Rheum. 2016;68(2):347-358.

2.       Buch MH, Bingham SJ, Seto Y, et al. Lack of response to anakinra in rheumatoid arthritis following failure of tumor necrosis factor α blockade. Arthritis Rheum. 2004;50:725–8.