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Published in: Inflammation 1-2/2007

01-04-2007

Effects of Resveratrol in Inflammatory Arthritis

Authors: N. Elmali, O. Baysal, A. Harma, I. Esenkaya, B. Mizrak

Published in: Inflammation | Issue 1-2/2007

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Abstract

Summary:

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.

Results:

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).

Conclusion:

This study suggests that intra-articular injection of resveratrol may protect cartilage against the development of experimentally induced IA.
Literature
1.
go back to reference Keffer, J., L. Probert, H. Cazlaris, S. Georgopoulos, E. Kaslaris, D. Kioussis, and G. Kollias. 1991. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10:4025–4031.PubMed Keffer, J., L. Probert, H. Cazlaris, S. Georgopoulos, E. Kaslaris, D. Kioussis, and G. Kollias. 1991. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10:4025–4031.PubMed
2.
go back to reference Alonzi, T., E. Fattori, D. Lazzaro, P. Costa, L. Probert, G. Kollias, F. De Benedetti, V. Poli, and G. Ciliberto. 1998. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187:461–468.PubMedCrossRef Alonzi, T., E. Fattori, D. Lazzaro, P. Costa, L. Probert, G. Kollias, F. De Benedetti, V. Poli, and G. Ciliberto. 1998. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187:461–468.PubMedCrossRef
3.
go back to reference Sweeney, S. E., and G. S. Firestein. 2004. Signal transduction in rheumatoid arthritis. Curr. Opin. Rheumatol. 16(3):231–237.PubMedCrossRef Sweeney, S. E., and G. S. Firestein. 2004. Signal transduction in rheumatoid arthritis. Curr. Opin. Rheumatol. 16(3):231–237.PubMedCrossRef
4.
go back to reference 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. 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.
5.
go back to reference Fujisawa, K., H. Aono, T. Hasunuma, K. Yamamoto, S. Mita, and K. Nishioka. 1996. Activation of transcription factor NF-kappa B in human synovial cells in response to tumor necrosis factor alpha. Arthritis Rheum. 39:197–203.PubMedCrossRef Fujisawa, K., H. Aono, T. Hasunuma, K. Yamamoto, S. Mita, and K. Nishioka. 1996. Activation of transcription factor NF-kappa B in human synovial cells in response to tumor necrosis factor alpha. Arthritis Rheum. 39:197–203.PubMedCrossRef
6.
go back to reference Marok, R., P. G. Winyard, A. Coumbe, M. L. Kus, K. Gaffney, and S. Blades, et al. 1996. Activation of the transcription factor nuclear factor-kB in human inflamed synovial tissue. Arthritis Rheum. 39:583–591.PubMedCrossRef Marok, R., P. G. Winyard, A. Coumbe, M. L. Kus, K. Gaffney, and S. Blades, et al. 1996. Activation of the transcription factor nuclear factor-kB in human inflamed synovial tissue. Arthritis Rheum. 39:583–591.PubMedCrossRef
7.
go back to reference 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).PubMedCrossRef 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).PubMedCrossRef
8.
go back to reference Pope, R. M. 2002. Apoptosis as a therapeutic tool in rheumatoid arthritis. Nat. Rev., Immunol. 2:527–535.CrossRef Pope, R. M. 2002. Apoptosis as a therapeutic tool in rheumatoid arthritis. Nat. Rev., Immunol. 2:527–535.CrossRef
9.
go back to reference Tak, P. P., D. M. Gerlag, K. R. Aupperle, D. A. van de Geest, M. Overbeek, and B. L. Bennett, et al. 2001. Inhibitor of nuclear factor kappaB kinase beta is a key regulator of synovial inflammation. Arthritis Rheum. 44(8):1897–1907.PubMedCrossRef Tak, P. P., D. M. Gerlag, K. R. Aupperle, D. A. van de Geest, M. Overbeek, and B. L. Bennett, et al. 2001. Inhibitor of nuclear factor kappaB kinase beta is a key regulator of synovial inflammation. Arthritis Rheum. 44(8):1897–1907.PubMedCrossRef
10.
go back to reference Bertelli, A. A., F. Ferrara, and G. Diana, et al. 1999. Resveratrol, a natural stilbene in grapes and wine, enhances intraphagocytosis in human promonocytes: a co-factor in antiinflammatory and anticancer chemopreventive activity. Int. J. Tissue React. 21:93–104.PubMed Bertelli, A. A., F. Ferrara, and G. Diana, et al. 1999. Resveratrol, a natural stilbene in grapes and wine, enhances intraphagocytosis in human promonocytes: a co-factor in antiinflammatory and anticancer chemopreventive activity. Int. J. Tissue React. 21:93–104.PubMed
11.
go back to reference Soleas, G. J., E. P. Diamandis, and D. M. Goldberg. 1997. Wine as a biological fluid: history, production, and role in disease prevention. J. Clin. Lab. Anal. 11:287–313.PubMedCrossRef Soleas, G. J., E. P. Diamandis, and D. M. Goldberg. 1997. Wine as a biological fluid: history, production, and role in disease prevention. J. Clin. Lab. Anal. 11:287–313.PubMedCrossRef
12.
go back to reference Jang, M., L. Cai, G. O. Udeani, K. V. Slowing, C. F. Thomas, C. W. Beecher, H. H. Fong, N. R. Farnsworth, A. D. Kinghorn, and R. G. Mehta, et al. 1997. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220.PubMedCrossRef Jang, M., L. Cai, G. O. Udeani, K. V. Slowing, C. F. Thomas, C. W. Beecher, H. H. Fong, N. R. Farnsworth, A. D. Kinghorn, and R. G. Mehta, et al. 1997. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220.PubMedCrossRef
13.
go back to reference 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.PubMed 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.PubMed
14.
go back to reference 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).PubMedCrossRef 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).PubMedCrossRef
15.
go back to reference Holmes-McNary, M., and A. S. Baldwin Jr. 2000. Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase. Cancer Res. 60(13):3477–3483 (July 1).PubMed Holmes-McNary, M., and A. S. Baldwin Jr. 2000. Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase. Cancer Res. 60(13):3477–3483 (July 1).PubMed
16.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
17.
go back to reference 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. 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.
18.
go back to reference Idogawa, H., A. Imamura, K. Matsuo, K. Yoshitake, T. Umemura, and M. Ohashi. 1998. A monoarthritis model in rabbits induced by repeated intra-articular injections of lipopolysaccharide. Int. J. Exp. Pathol. 79:93–104.PubMedCrossRef Idogawa, H., A. Imamura, K. Matsuo, K. Yoshitake, T. Umemura, and M. Ohashi. 1998. A monoarthritis model in rabbits induced by repeated intra-articular injections of lipopolysaccharide. Int. J. Exp. Pathol. 79:93–104.PubMedCrossRef
19.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
20.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
21.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
22.
go back to reference Gerlag, D. M., L. J. Ransone, D. L. Boyle, P. P. Tak, A. M. Manning, and G. S. Firestein. 2000. Effect of a T cell specific NF-kB inhibitor on in vitro cytokine production and collagen-induced arthritis. J. Immunol. 165:1652–1658.PubMed Gerlag, D. M., L. J. Ransone, D. L. Boyle, P. P. Tak, A. M. Manning, and G. S. Firestein. 2000. Effect of a T cell specific NF-kB inhibitor on in vitro cytokine production and collagen-induced arthritis. J. Immunol. 165:1652–1658.PubMed
23.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
24.
go back to reference Martinez, J., and J. J. Moreno. 2000. Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem. Pharmacol. 59(7):865–870.PubMedCrossRef Martinez, J., and J. J. Moreno. 2000. Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem. Pharmacol. 59(7):865–870.PubMedCrossRef
25.
go back to reference Bertelli, A., A. A. Bertelli, A. Gozzini, and L. Giovannini. 1998. Plasma and tissue resveratrol concentrations and pharmacological activity. Drugs Exp. Clin. Res. 24:133–138.PubMed Bertelli, A., A. A. Bertelli, A. Gozzini, and L. Giovannini. 1998. Plasma and tissue resveratrol concentrations and pharmacological activity. Drugs Exp. Clin. Res. 24:133–138.PubMed
26.
Metadata
Title
Effects of Resveratrol in Inflammatory Arthritis
Authors
N. Elmali
O. Baysal
A. Harma
I. Esenkaya
B. Mizrak
Publication date
01-04-2007
Published in
Inflammation / Issue 1-2/2007
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-006-9012-0

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