There are many similarities in inflammatory responses observed in atherosclerosis and rheumatoid arthritis (RA). Chemokines and their receptors are important in both diseases. The long-term objectives of this application are to study the clinical and biological effects of C-C chemokine receptor 2 (CCR2) and CCR1/CCR5 antagonists in rodent arthritis. Furthermore we plan to determine the effect of key proinflammatory (TNF-alpha and IL-1beta) and Th1 promoting (IL-12 and IL-18) cytokines on CCR5 and CCR2 post-receptor signaling events in the 2D61L-12 T cell line and endothelial cells in the presence of CCR5/CCR2 antagonists. Using CCR2/CCR5 antagonists in a model of inflammatory disease (RA) in vivo in addition to the knowledge acquired from studying the mechanism of proinflammatory cytokines effects on CCR2/CCR5 signaling pathways in vitro will help us understand and design more efficient in vivo studies in both RA and atherosclerosis. Several studies have used antagonists, binding proteins and antisense sequences to target proinflammatory cytokines, including TNF-alpha (antagonist; Etanercept), IL-18 (binding protein) and chemokine receptors CCR2/CCR5 (antagonists, antibodies and gene knockouts) in hope of mitigating the inflammatory reaction in atherosclerosis and RA. In order to investigate the effect of IL-12 and IL-18 on CCR5 and the effect of TNF-alpha, IL-1beta and IL-8 on CCR2 downstream signaling pathways, we will immunoprecipitate CC chemokine receptors in cytokine treated cells and detect associated pathways by Western blot analysis. The purpose of using CCR antagonists is to validate that the cytokines exert their effect through these receptors. Additionally we will use CCR2/CCR5 antagonists in an in vivo inflammatory model of RA (rat adjuvant induced arthritis (AIA)) to examine their ability to decrease the severity and delay the onset of the disease. For this purpose we will determine the progression of indicators of inflammation, such as arthritis index, joint circumference, paw volume, joint count, arthritis severity, cell type recruitment and markers of bone destruction. Achieving these goals may give us valuable information in regard to molecular inflammatory mechanisms involved in atherosclerosis and RA.
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| Shahrara, Shiva; Proudfoot, Amanda E I; Park, Christy C et al. (2008) Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis. J Immunol 180:3447-56 |
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| Shahrara, Shiva; Castro-Rueda, Hernan P; Haines, G Kenneth et al. (2007) Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues. Arthritis Res Ther 9:R112 |
| Shahrara, Shiva; Park, Christy C; Temkin, Vladislav et al. (2006) RANTES modulates TLR4-induced cytokine secretion in human peripheral blood monocytes. J Immunol 177:5077-87 |
| Shahrara, Shiva; Proudfoot, Amanda E I; Woods, James M et al. (2005) Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum 52:1907-19 |
| Shahrara, Shiva; Amin, Mohammad A; Woods, James M et al. (2003) Chemokine receptor expression and in vivo signaling pathways in the joints of rats with adjuvant-induced arthritis. Arthritis Rheum 48:3568-83 |
