Rheumatoid arthritis (RA) is a chronic inflammatory disease of the articular joints. A systemic inflammatory milieu generated by high levels of pro-inflammatory cytokines, interleukin-6 (IL-6) in particular, drives the inflammation and synovial cell activation that characterize joint destruction and extra-articular co-morbidities including cardiovascular diseases. IL-6 is a pleiotropic cytokine that transmits its signal via membrane- bound IL-6 receptor (IL-6R) and glycoprotein130 (gp130). IL-6 plays an important role in transition of synovial inflammation into systemic inflammation by inducing the synthesis of acute reactive proteins (ARPs), RANKL, and matrix degrading enzymes (MMP-2, -13). These proteins also contribute to the vascular and joint damage observed in RA. The only therapy developed against IL-6, tocilizumab, has shown efficacy in RA treatment. However, its use is limited due to severe adverse events such as elevated cholesterol and liver toxicity, and the high healthcare costs associated with continuous intravenous administration. These issues make it important to develop small molecule inhibitors of IL-6 for the treatment of RA. Epigallotcatechin-3-gallate (EGCG), a potent anti-inflammatory polyphenol found in green tea, blocks IL-1?-induced IL-6 synthesis in human RA synovial fibroblasts (RA-FLS). Further, EGCG significantly inhibited IL-1?-induced mgp130 expression with concomitant stimulation of soluble gp130 (sgp130) production as an endogenous IL-6 inhibitor. In our preliminary findings, IL-6/sIL-6R-induced expression of RANKL and Cadherin-11 (CAD-11) in RA-FLS was inhibited by EGCG pretreatment. IL-6 levels are several-fold higher than those of IL-1? or tumor necrosis factor (TNF)-? in the serum and joints of adjuvant-induced arthritis (AIA) rats, and EGCG ameliorated arthritis via selective inhibition of IL-6. IL-6 driven systemic CRP levels were observed to peak with the severity of arthritis in rat AIA suggesting an important role of IL-6 in promoting systemi inflammation leading to vascular dysfunction in RA. Based on these novel findings, we will study the mechanisms through which EGCG inhibits IL-6 mediated inflammation and bone destruction in arthritis and suppresses vascular dysfunction in rat AIA. The success of these studies will lead to two clinically important findings: (1) The identification of IL-6 as a therapeutic target t alleviate vascular dysfunction in RA, and (2) EGCG's ability to suppress IL-6 mediated synovial and systemic inflammation and to inhibit vascular damage associated with RA. Successful completion of this study will lay the foundation for testing EGCG as a treatment option for RA and other inflammatory diseases.

Public Health Relevance

Rheumatoid arthritis (RA), a chronic inflammatory joint disorder, is a leading cause of work-related disabilities and a significant socio-economic health challenge due to expensive, yet incomplete, conventional therapies. Using synovial fibroblasts isolated from RA patients and an animal model of human RA, we propose to test the efficacy of epigallocatechin-3-gallate (EGCG), a potential anti-inflammatory molecule found in green tea, in regulating interleukin-6 (IL-6) synthesis and its detrimental effects in RA. The success of the proposed experiments may lead to a significant advancement in the development of EGCG as a potentially safe and inexpensive treatment option for RA.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Mao, Su-Yau
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University of Toledo
Schools of Pharmacy
United States
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Cottier, Karissa E; Fogle, Elise M; Fox, David A et al. (2014) Noxa in rheumatic diseases: present understanding and future impact. Rheumatology (Oxford) 53:1539-46