Effects of Resveratrol in Inflammatory Arthritis
Nuclear factor kappa B (NF-κB), is a pivotal transcription factor involved in the activation of the TNF-α and IL-1β genes. Activation of NF-κB in synovial cells is a feature seen in arthritis patients. Resveratrol, a polyphenolic, natural phytoalexin found with particularly high levels in grape skin and red wine is potent and specific inhibitor of TNF-α and IL-1β induced NF-κB activation. We aimed to determine the in vivo effects of intra-articular injections of resveratrol on cartilage and synovium in an experimental rabbit inflammatory arthritis model.
Materials and methods:
Arthritis was induced by intra-articular injection of three times of 50 μg lipopolysaccharide (LPS) at day 0, 4 and 8 at 4-day intervals into the knee joints of rabbits. To the test group, 10 μMol/kg resveratrol in the DMSO was injected in the knees at day 0 and then it was continued once daily for 2 weeks. To the control group the same time and amount of DMSO was injected the knees of rabbits. All rabbits were killed 1 week after the last injection and cartilage tissue and synovium were evaluated with semiquantitative scoring histologically.
According to control group in the resveratrol group, significantly decreased cartilage destruction was determined by H&E staining (p = 0.04). Loss of matrix proteoglycan content in the cartilage was much lower, as determined by safranin O staining (p = 0.03). We also observed marked synovial inflammation after intra-articular injection to control knees, but not in the resveratrol treated group knees (p = 0.01).
This study suggests that intra-articular injection of resveratrol may protect cartilage against the development of experimentally induced IA.
Key wordsresveratrol cartilage synovium inflammatory arthritis NF-κB
- 4.Feldmann, M., F. M. Brennan, B. M. Foxwell, and R. N. Maini. 2001. The role of TNF alpha and IL-1 in rheumatoid arthritis. Curr. Dir. Autoimmun. 3:99–188.Google Scholar
- 7.Yamamoto, K., T. Arakawa, N. Ueda, and S. Yamamoto. 1995. Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells. J. Biol. Chem. 270(52):31315–31320 (Dec 29).PubMedCrossRefGoogle Scholar
- 13.Manna, S. K., A. Mukhopadhyay, and B. B. Aggarwal. 2000. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappaB, activator protein-1 and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J. Immunol. 164:6509–6519.PubMedGoogle Scholar
- 14.Estrov, Z., S. Shishodia, S. Faderl, D. Harris, Q. Van, H. M. Kantarjian, M. Talpaz, and B. B. Aggarwal. 2003. Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. Blood 102(3):987–995 (Aug. 1).PubMedCrossRefGoogle Scholar
- 16.Subbaramaiah, K., W. J. Chung, P. Michaluart, N. Telang, T. Tanabe, H. Inoue, M. Jang, J. M. Pezzuto, and A. J. Dannenberg. 1998. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J. Biol. Chem. 273:21875–21882.PubMedCrossRefGoogle Scholar
- 17.Surh, Y. J., K. S. Chun, H. H. Cha, S. S. Han, Y. S. Keum, K. K. Park, and S. S. Lee. 2001. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat. Res. 480–481:243–268.Google Scholar
- 19.Plater-Zyberk, C., L. A. B. Joosten, M. M. A. Helsen, P. Sattonnet-Roche, C. Siegfried1, S. Alouani, F. A. J. van de Loo, P. Graber, S. Aloni, R. Cirillo, E. Lubberts, C. A. Dinarello, W. B. van den Berg, and Y. Chvatchko. 2001. Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis. J. Clin. Invest. 108(12):1825–1832.PubMedCrossRefGoogle Scholar
- 20.Joosten, L. A. B., E. Lubberts, M. M. A. Helsen, T. Saxne, C. J. J. Coenen-de Roo, D. Heinegård, and W. B. van den Berg. 1999. Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis. Arthritis Res. 1(1):81–91.PubMedCrossRefGoogle Scholar
- 21.Miagkov, A. V., D. V. Kovalenko, C. E. Brown, J. R. Didsbury, J. P. Cogswell, S. A. Stimpson, A. S. Baldwin, and S. S. Makarov. 1998. NF-kB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc. Natl. Acad. Sci. USA 95:13859–13864.PubMedCrossRefGoogle Scholar
- 23.Bondeson, J., B. Foxwell, F. Brennan, and M. Feldmann. 1999. Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proc. Natl. Acad. Sci. USA 96:5668–5673.PubMedCrossRefGoogle Scholar