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Swertiamarin ameliorates inflammation and osteoclastogenesis intermediates in IL-1β induced rat fibroblast-like synoviocytes

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Abstract

Objective and design

Rheumatoid arthritis is a chronic inflammatory and autoimmune disease that leads to aggressive joint cartilage and bone destruction. Swertiamarin is a secoiridoid glycoside found in Enicostema axillare (Lam) A. Raynal, a medicinal plant used in the Indian system of traditional medicine. In the present study, the potential of swertiamarin was evaluated in IL-1β induced fibroblast-like synoviocytes (FLS).

Methods

The FLS were isolated from Freund’s Complete Adjuvant induced arthritic (AA) rats and cultured with IL-1β. The normal FLS and AA-FLS were cultured and used for subsequent experiment in fibroblastic morphology form. The efficacy of swertiamarin (10–50 μg/ml) was evaluated on mRNA and protein expression levels of inflammatory and osteoclastogenesis mediators. The efficacy was also evaluated on p38 MAPKα levels with time course studies (2, 4, 6, 8 and 12 h).

Results

IL-1β induced cell proliferation (149.46 ± 13.73 %) and NO production (162.03 ± 11.03 %) in AA-FLS; treatment with swertiamarin controlled proliferation (82.77 ± 4.22 %) and NO production (82.06 ± 3.91 % at 50 μg/ml) in a dose-dependent manner. It also significantly (P < 0.05) modulated the expression of apoptotic marker (caspase 3), proinflammation mediators (TNFα, IL-6, PGE2, COX-2, iNOS, MMPs) and osteoclastogenic mediator (RANKL) at both the mRNA and protein levels. Treatment with swertiamarin inhibited the levels of p38 MAPKα in a dose-dependent manner and also significantly (P < 0.05) attenuated the release of the same in time dependent mode.

Conclusion

These findings suggest that treatment with swertiamarin attenuated IL-1β induced FLS, and it revealed anti-inflammatory potential by attenuating aggressive FLS.

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References

  1. Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233(1):233–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Shankar S, Handa R. Bone Health in Asian women with rheumatoid arthritis. US Musculoskelet Rev. 2010;5:33–5.

    Google Scholar 

  3. Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. In: Firestein GS, Budd RC, Harris T, McInnes IB, Ruddy S, Sergent JS, editors. Kelly’s textbook of rheumatology 8. Philadelphia: Saunders Elsevier; 2009. p. 1035–86.

    Chapter  Google Scholar 

  4. Mountz JD, Zhang HG. Regulation of apoptosis of synovial fibroblasts. Curr Dir Autoimmun. 2001;3:216–39.

    Article  CAS  PubMed  Google Scholar 

  5. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656–64.

    Article  CAS  PubMed  Google Scholar 

  6. Lee S-J, Nam W-D, Na H-J, Cho Y-L, Ha K-S, Hwang J-Y, Lee H, Kim S-O, Kwon Y-G, Kim Y-M. CT20126, a novel immunosuppressant, prevents collagen-induced arthritis through the down-regulation of inflammatory gene expression by inhibiting NF-kB activation. Biochem Pharmacol. 2008;76:79–90.

    Article  CAS  PubMed  Google Scholar 

  7. Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodontal. 2005;40(4):287–93.

    Article  CAS  Google Scholar 

  8. Korb A, Tohidast-Akrad M, Cetin E, Axmann R, Smolen J, Schett G. Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis. Arthritis Rheum. 2006;54:2745–56.

    Article  CAS  PubMed  Google Scholar 

  9. Mbalaviele G, Anderson G, Jones A, Ciechi PD, Settle S, Mnich S, Thiede M, Abu-Amer Y, Portanova J, Monahan J. Inhibition of p38 mitogenactivated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther. 2006;317:1044–53.

    Article  CAS  PubMed  Google Scholar 

  10. Huh J-E, Hong J-M, Baek Y-H, Lee J-D, Choi D-Y, Park D-S. Anti-inflammatory and anti-nociceptive effect of Betula platyphylla var. japonica in human interleukin-1β-stimulated fibroblast-like synoviocytes and in experimental animal models. J Ethnopharmacol. 2011;135:126–34.

    Article  PubMed  Google Scholar 

  11. Magora HB, Rahman MM, Gray AI, Cole MD. Swertiamarin from Enicostemma axillere subsp. axillere (Gentianaceae). Biochem Syst Ecol. 2003;31:553–5.

    Article  CAS  Google Scholar 

  12. Saravanan S, Prakash Babu N, Pandikumar P, Gabriel Paulraj M, Karunairaj M, Ignacimuthu S. Immunomodulatory potential of Enicostema axillare (Lam.) A. Raynal, a traditional medicinal Plant. J Ethnopharmacol. 2012;140:239–46.

    Article  CAS  PubMed  Google Scholar 

  13. Vaidya H, Giri S, Jain M, Goyal R. Decrease in serum matrix metalloproteinase-9 and matrix metalloproteinase-3 levels in Zucker fa/fa obese rats after treatment with swertiamarin. Exp Clin Cardiol. 2012;17(1):12–6.

    PubMed Central  PubMed  Google Scholar 

  14. Jaishree V, Badami S. Antioxidant and hepatoprotective effect of swertiamarin from Enicostemma axillare against D-galactosamine induced acute liver damage in rats. J Ethnopharmacol. 2010;130(1):103–6.

    Article  CAS  PubMed  Google Scholar 

  15. Jaishree V, Badami S, Rupesh Kumar M, Tamizhmani T. Antinociceptive activity of swertiamarin isolated from Enicostemma axillare. Phytomedicine. 2009;16(2–3):227–32.

    Article  CAS  PubMed  Google Scholar 

  16. Vaijanathappa J, Badami S. Antiedematogenic and free radical scavenging activity of swertiamarin isolated from Enicostemma axillare. Planta Med. 2009;75(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  17. Park KS, Kim BH, Chang IM. Inhibitory potencies of several iridoids on cyclooxygenase-1, cyclooxygnase-2 enzymes activities, tumor necrosis factor-α and nitric oxide production in vitro. Evid Based Compl Alt. 2010;7(1):41–5.

    Article  Google Scholar 

  18. Wei S, Chen G, He W, Chi H, Abe H, Yamashita K, Yokoyama M, Kodama H. Inhibitory effects of secoiridoids from the roots of Gentiana straminea on stimulus-induced superoxide generation, phosphorylation and translocation of cytosolic compounds to plasma membrane in human neutrophils. Phytother Res. 2012;26(2):168–73.

    Article  CAS  PubMed  Google Scholar 

  19. Kimura Y, Sumiyoshi M. Effects of Swertia japonica extract and its main compound swertiamarin on gastric emptying and gastrointestinal motility in mice. Fitoterapia. 2011;82(6):827–33.

    Article  CAS  PubMed  Google Scholar 

  20. Hou Y, Wu J, Huang Q, Guo L. Luteolin inhibits proliferation and affects the function of stimulated rat synovial fibroblasts. Cell Biol Int. 2009;33:135–47.

    Article  CAS  PubMed  Google Scholar 

  21. Yang XY, Liu CH, Liang X, Sun J. Effects of mineralization liquid on rat’s osteoblast proliferation and differentiation. Hua Xi Kou Qiang Yi Xue Za Zhi (West China J stomatol). 2008;26:656–9.

    Google Scholar 

  22. Ignacio SRN, Ferreira JLP, Almeida MB, Kubelka CF. Nitric oxide production by murine peritoneal macrophages in vitro and in vivo treated with Phyllanthus tenellus extracts. J Ethnopharmacol. 2001;74:181–7.

    Article  CAS  PubMed  Google Scholar 

  23. Adbul BH, Al-Zubairi AS, Tailan ND. Anticancer activity of natural compound (Zerumbone) extracted from Zingiber zerumbet in human HeLa cervical cancer cells. Int J Pharm. 2008;4(3):160–8.

    Article  Google Scholar 

  24. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−∆∆CT method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  25. Muller-Ladner U, Ospelt C, Gay S, Distler O, Pap T. Cells of the synovium in rheumatoid arthritis. Arthritis Res Ther. 2007;9:223.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Söderlin MK, Kautiainen H, Skogh T, Leirisalo-Repo M. Quality of life and economic burden of illness in very early arthritis. Population based study in southern Sweden. J Rheumatol. 2004;31:1717–22.

    PubMed  Google Scholar 

  27. Lee JI, Burckart GJ. Nuclear factor kappa B: important transcription factor and therapeutic target. J Clin Pharmacol. 1998;38:981–93.

    Article  CAS  PubMed  Google Scholar 

  28. Makarov SS. NF-kB in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res. 2001;3:200–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Verpoorte R. Exploration of nature’s chemodiversity: the role of secondary metabolites as leads in drug development. Drug Discov Today. 1999;3:232–8.

    Article  Google Scholar 

  30. Li R, Cai L, Xie X-F, Peng L, Li J. 7,3′-dimethoxy hesperetin induces apoptosis of fibroblast-like synoviocytes in rats with adjuvant arthritis through caspase 3 activation. Phytother Res. 2010;24:1850–6.

    Article  CAS  PubMed  Google Scholar 

  31. Ospelt C, Neidhart M, Gay RE, Gay S. Synovial activation in rheumatoid arthritis. Front Biosci. 2004;9:2323–34.

    Article  CAS  PubMed  Google Scholar 

  32. Seemayer CA, Neidhart M, Jungel A, Gay RE, Gay S. Synovial fibroblasts in joint destruction of rheumatoid arthritis. Drug Discov Today Dis Mech. 2005;2:359–65.

    Article  Google Scholar 

  33. Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42.

    Article  CAS  PubMed  Google Scholar 

  34. Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104.

    Article  CAS  PubMed  Google Scholar 

  35. Goldring SR. Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology. 2003;42:11–6.

    Article  Google Scholar 

  36. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.

    Article  CAS  PubMed  Google Scholar 

  37. Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev. 2002;23:90–119.

    Article  CAS  PubMed  Google Scholar 

  38. Murakami M, Nishimoto N. Osteoimmunology-basic principles and clinical applications-inflammatory cytokines in rheumatoid arthritis. Clin Calcium. 2012;22(11):1737–46.

    CAS  PubMed  Google Scholar 

  39. Gay S, Kuchen S, Gay RE, Neidhart M. Cartilage destruction in rheumatoid arthritis. Ann Rheum Dis. 2002;61(2):87.

    Google Scholar 

  40. Choi EM, Lee YS. Luteolin suppresses IL-1β-induced cytokines and MMPs production via p38 MAPK, JNK, NF-kappaB and AP-1 activation in human synovial sarcoma cell line, SW982. Food Chem Toxicol. 2010;48:2607–11.

    Article  CAS  PubMed  Google Scholar 

  41. Lin N, Liu C, Xia C, Jia H, Imada K, Wu H, Ito A. Triptolide, a diterpenoid triepoxide, suppresses inflammation and cartilage destruction in collagen-induced arthritis mice. Biochem Pharmacol. 2007;73:136–46.

    Article  CAS  PubMed  Google Scholar 

  42. Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L, Isakson P. Pharmacological and biochemical demonstration of the role of cyclooxygenase-2 in inflammation and pain. P Natl Acad Sci USA. 1994;91:12013–7.

    Article  CAS  Google Scholar 

  43. Kim JY, Lee EY, Lee EB, Lee YJ, Yoo HJ, Choi J, Song YW. Atorvastatin inhibit osteoclastogenesis by decreasing the expression of RANKL in the synoviocytes of rheumatoid arthritis. Arthritis Res Ther. 2012;14:R187.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Lee HY, Jeon HS, Song EK, Han MK, Park SI, Lee SI, Yun HJ, Kim JR, Kim JS, Lee YC, Kim SI, Kim HR, Choi JY, Kang I, Kim HY, Yoo WH. CD40 ligation of rheumatoid synovial fibroblasts regulates RANKL-mediated osteoclastogenesis: evidence of NF-kappaB-dependent, CD40-mediated bone destruction in rheumatoid arthritis. Arthritis Rheum. 2006;54:1747–58.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Financial assistance in the form of a Senior Research Fellowship given by Indian Council for Medical Research (No. 45/81/2011/BMS/TRM), New Delhi to the first author is gratefully acknowledged. We thank the Entomology Research Institute, Loyola College, Chennai for financial assistance.

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The authors declare that they have no conflict of interest.

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Correspondence to S. Ignacimuthu.

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Responsible Editor: Liwu Li.

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Saravanan, S., Hairul Islam, V.I., Thirugnanasambantham, K. et al. Swertiamarin ameliorates inflammation and osteoclastogenesis intermediates in IL-1β induced rat fibroblast-like synoviocytes. Inflamm. Res. 63, 451–462 (2014). https://doi.org/10.1007/s00011-014-0717-5

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  • DOI: https://doi.org/10.1007/s00011-014-0717-5

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