RHO-ISO-ALPHA ACIDS AND TETRAHYDRO-ISO-ALPHA ACIDS ARE SELECTIVE PROTEIN KINASE INHIBITORS WHICH POTENTLY REDUCE INFLAMMATION IN MACROPHAGES IN VITRO AND IN THE COLLAGEN-INDUCED RHEUMATOID ARTHRITIS MODEL IN VIVO
An emerging area of science is focused on identifying phytochemicals with anti-inflammatory activity. We previously discovered that modified hop extracts from Humulus lupulus, rho-iso-alpha acids (RIAA) and tetrahydro-iso-alpha acids (THIAA), possessed anti-inflammatory potential. In this study, we focused on understanding their mode of action in a series of experiments. First, we found that both RIAA and THIAA inhibited prostaglandin E2 (PGE2) production in lipopolysaccharide-stimulated RAW 264.7 macrophages by inhibiting inducible cyclooxygenase-2 (COX-2) protein expression. Second, in the same cell model we found that RIAA and THIAA dose-dependently reduced NF-B nuclear translocation and abundance. Third, to assess their effects on inflammatory signal transduction pathways, we analyzed RIAA and THIAA against several human protein kinases in cell-free enzyme assays. Both selectively inhibited kinases involved in inflammatory signal transduction, including SyK, PI3K, and . These kinases are involved in Fc receptors and B cell receptor signaling, and are therapeutic targets in asthma, allergy and rheumatoid arthritis. Finally, to determine the therapeutic potential of RIAA and THIAA in rheumatoid arthritis, they were tested in the collagen-induced arthritis model. DBA/J mice were immunized with bovine type II collagen for 3 weeks. Mice demonstrating the onset of inflammation were randomized and therapy initiated. The joint swelling was measured for the next 2 weeks to determine the extent of disease. Both RIAA and THIAA dose-dependently reduced the arthritis index and joint degradation, and at a dose of 250 mg/kg, their efficacy was similar to that of 20 mg/kg of celecoxib, the positive control. These hop-derived molecules may be of great value as an efficacious and safer alternative to treat chronic inflammation.
Tripp, M.L., Konda, V.R., Darland, G., Desai, A., Chang, J.-L., Carroll, B.J. and Bland, J.S. (2009). RHO-ISO-ALPHA ACIDS AND TETRAHYDRO-ISO-ALPHA ACIDS ARE SELECTIVE PROTEIN KINASE INHIBITORS WHICH POTENTLY REDUCE INFLAMMATION IN MACROPHAGES IN VITRO AND IN THE COLLAGEN-INDUCED RHEUMATOID ARTHRITIS MODEL IN VIVO . Acta Hortic. 848, 221-234
hops, Humulus lupulus, cyclooxygenase, prostaglandin E2, NF-κB, anti-inflammatory activity, protein kinases