Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder in which activated synovial fibroblasts produce chemokines that facilitate the invasion of the articular cartilage and underlying bone by the release of matrix-degrading enzymes. Importantly, RANTES/CCL5 and macrophage inflammatory protein (MIP-11)/CCL3 are the chemokines shown to activate CCR1 and CCR5 receptor to attract T cells and monocytes into joints during the onset of disease. Thus, regulation of CCR1/CCR5 receptor expression is emerging as a novel therapeutic strategy for RA. In our preliminary findings, epigallocatechin-3-gallate (EGCG), a potent anti-inflammatory molecule, blocked interleukin-12 (IL-12)-induced RANTES/CCL5 and MIP-11/CCL3 ) production in RA synovial fibroblasts that are mediated via CCR1/CCR5 receptors. EGCG also inhibited IL-12-induced markers of cartilage and bone destruction (IL-6, VEGF, and PGE2), and matrix degrading enzyme matrix metalloproteinase-2 (MMP-2) activity in human RA synovial fibroblasts. [An in vivo study showed that EGCG prevented adjuvant-induced arthritis (AIA) in rats.] This proposal capitalizes on these novel observations. The central hypothesis of the work proposed is that EGCG inhibits cell recruitment, angiogenesis and joint destruction in rat adjuvant-induced arthritis (AIA) model and in RA synovial tissue (ST)-severe combined immunodeficient (SCID) chimera by blocking CCR1/CCR5 receptor expression.
In Aim 1, we will test whether EGCG inhibits CCR1/CCR5 receptor expression to suppress RANTES/CCL5 or MIP-11/CCL3 activity and angiogenesis in RA ST explants.
In Aim 2, we will study if EGCG blocks CCR1/CCR5 receptor mediated cell recruitment and tissue invasion in a human RA ST- severe combined immunodeficiency (SCID) mouse chimera. Finally, in Aim 3, we will determine whether EGCG downregulates CCR1/CCR5 receptor expression to inhibit angiogenesis, and cartilage and bone destruction in a rat AIA model of RA. The success of the proposed experiments may lead to a significant advancement in the development of EGCG as a potential treatment option for RA and possibly other autoimmune diseases. PROJECT NARRATIVE 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 animal models of human RA, we propose to test the efficacy of epigallocatechin-3-gallate (EGCG), a potential anti-inflammatory molecule found in green tea, in inhibiting the destruction of the cartilage and bone 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)
Small Research Grants (R03)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-EHB-H (M1))
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
Zip Code
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
Ahmed, Salahuddin; Riegsecker, Sharayah; Beamer, Maria et al. (2013) Largazole, a class I histone deacetylase inhibitor, enhances TNF-?-induced ICAM-1 and VCAM-1 expression in rheumatoid arthritis synovial fibroblasts. Toxicol Appl Pharmacol 270:87-96
Jones, Brian A; Riegsecker, Sharayah; Rahman, Ayesha et al. (2013) Role of ADAM-17, p38 MAPK, cathepsins, and the proteasome pathway in the synthesis and shedding of fractalkine/CX? CL1 in rheumatoid arthritis. Arthritis Rheum 65:2814-25
Riegsecker, Sharayah; Wiczynski, Dustin; Kaplan, Mariana J et al. (2013) Potential benefits of green tea polyphenol EGCG in the prevention and treatment of vascular inflammation in rheumatoid arthritis. Life Sci 93:307-12
Marotte, Hubert; Ruth, Jeffrey H; Campbell, Phillip L et al. (2010) Green tea extract inhibits chemokine production, but up-regulates chemokine receptor expression, in rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis. Rheumatology (Oxford) 49:467-79
Jones, Brian A; Beamer, Maria; Ahmed, Salahuddin (2010) Fractalkine/CX3CL1: a potential new target for inflammatory diseases. Mol Interv 10:263-70
Ahmed, Salahuddin (2010) Green tea polyphenol epigallocatechin 3-gallate in arthritis: progress and promise. Arthritis Res Ther 12:208
Marotte, Hubert; Ahmed, Salahuddin; Ruth, Jeffrey H et al. (2010) Blocking ERK-1/2 reduces tumor necrosis factor alpha-induced interleukin-18 bioactivity in rheumatoid arthritis synovial fibroblasts by induction of interleukin-18 binding protein A. Arthritis Rheum 62:722-31
Ahmed, Salahuddin; Silverman, Matthew D; Marotte, Hubert et al. (2009) Down-regulation of myeloid cell leukemia 1 by epigallocatechin-3-gallate sensitizes rheumatoid arthritis synovial fibroblasts to tumor necrosis factor alpha-induced apoptosis. Arthritis Rheum 60:1282-93