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.
Similar content being viewed by others
References
Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233(1):233–55.
Shankar S, Handa R. Bone Health in Asian women with rheumatoid arthritis. US Musculoskelet Rev. 2010;5:33–5.
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.
Mountz JD, Zhang HG. Regulation of apoptosis of synovial fibroblasts. Curr Dir Autoimmun. 2001;3:216–39.
Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656–64.
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.
Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodontal. 2005;40(4):287–93.
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.
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.
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.
Magora HB, Rahman MM, Gray AI, Cole MD. Swertiamarin from Enicostemma axillere subsp. axillere (Gentianaceae). Biochem Syst Ecol. 2003;31:553–5.
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.
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.
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.
Jaishree V, Badami S, Rupesh Kumar M, Tamizhmani T. Antinociceptive activity of swertiamarin isolated from Enicostemma axillare. Phytomedicine. 2009;16(2–3):227–32.
Vaijanathappa J, Badami S. Antiedematogenic and free radical scavenging activity of swertiamarin isolated from Enicostemma axillare. Planta Med. 2009;75(1):12–7.
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.
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.
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.
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.
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.
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.
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.
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.
Muller-Ladner U, Ospelt C, Gay S, Distler O, Pap T. Cells of the synovium in rheumatoid arthritis. Arthritis Res Ther. 2007;9:223.
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.
Lee JI, Burckart GJ. Nuclear factor kappa B: important transcription factor and therapeutic target. J Clin Pharmacol. 1998;38:981–93.
Makarov SS. NF-kB in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res. 2001;3:200–6.
Verpoorte R. Exploration of nature’s chemodiversity: the role of secondary metabolites as leads in drug development. Drug Discov Today. 1999;3:232–8.
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.
Ospelt C, Neidhart M, Gay RE, Gay S. Synovial activation in rheumatoid arthritis. Front Biosci. 2004;9:2323–34.
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.
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.
Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104.
Goldring SR. Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology. 2003;42:11–6.
McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.
Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev. 2002;23:90–119.
Murakami M, Nishimoto N. Osteoimmunology-basic principles and clinical applications-inflammatory cytokines in rheumatoid arthritis. Clin Calcium. 2012;22(11):1737–46.
Gay S, Kuchen S, Gay RE, Neidhart M. Cartilage destruction in rheumatoid arthritis. Ann Rheum Dis. 2002;61(2):87.
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.
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.
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.
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.
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.
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.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Responsible Editor: Liwu Li.
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00011-014-0717-5