The use of complementary and alternative medicine approaches is becoming increasingly popular with rheumatoid arthritis (RA) patients. RA is a chronic inflammatory disease affecting approximately 1.0% of the American population and is a significant health and socio-economic challenge. In RA, activated synovial fibroblasts invade the articular cartilage and bone by a network of adhesion molecules and chemokines working in concert to induce inflammation and the release of matrix-degrading enzymes. In our preliminary studies, we found that the polyphenol-rich aqueous fraction of green tea (Camellia sinensis; green tea polyphenols, GTP) blocked interleukin-1? (IL-1?)-induced (i) production of the CC [monocyte chemotactic protein 1 (MCP-1) and regulated upon activation normally T cells expressed and secreted (RANTES] and CXC [IL-8 and growth regulated oncogene-a (Gro-a)] chemokines, (ii) cyclooxygenase-2 (COX-2) expression, and (iii) nuclear translocation of nuclear factor-kBp65 (NF-kBp65) in human RA synovial fibroblasts in vitro. In addition, treatment with GTP significantly blocked both constitutive- and IL-1?-induced matrix metalloproteinase-2 (MMP-2) activity in RA synovial fibroblasts in vitro. This proposal capitalizes on these novel observations. The central hypothesis of the work proposed in this application is that GTP will inhibit RA synovial fibroblast invasion by blocking chemokine production, cell adhesion, and MMP activation.
In specific aim 1, using RA synovial fibroblasts, we will study whether GTP inhibits chemokine production by inhibiting/altering IL-1? induced signaling pathways and the expression of chemokine receptors.
In specific aim 2, we will test whether GTP suppresses RA synovial fibroblast invasion by blocking IL-1? induced (a) expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), (b) signaling pathways implicated in MMP-2, -3, and -13 activation, and (c) COX-2 expression.
In specific aim 3, we will study whether GTP is effective in inhibiting chemokine mediated cell migration and MMP activation in RA synovial fibroblasts. Results from these studies will lay the foundation for in vivo studies for GTP as therapeutic entity to target chemokines and their receptor mediated synovial invasion in rodent arthritis models and in human RA. ? ? ?
