Advertisement

Immunologic Research

, Volume 64, Issue 4, pp 1071–1086 | Cite as

Majoon ushba, a polyherbal compound, suppresses pro-inflammatory mediators and RANKL expression via modulating NFкB and MAPKs signaling pathways in fibroblast-like synoviocytes from adjuvant-induced arthritic rats

  • Ramamoorthi Ganesan
  • Hari Madhuri Doss
  • Mahaboobkhan RasoolEmail author
Original Article

Abstract

Fibroblast-like synoviocytes (FLS) are inhabitant mesenchymal cells of synovial joints and have been recognized to play an imperative role in the immunopathogenesis of rheumatoid arthritis (RA). Blocking these pathological roles of FLS provides a potentially important therapeutic strategy for the treatment for RA. A recent study had confirmed that majoon ushba (MU), a polyherbal unani compound, possesses anti-arthritic effects in in vivo. Toward this direction, an effort has been made to understand the effect of MU on FLS derived from adjuvant-induced arthritis (AIA) rats. Here, we observed that MU administration (100–300 µg/ml) significantly inhibited the expression and phosphorylation of NFкB-p65 protein similar to that of the Bay 11-7082 (NFкB inhibitor) in NFкB signaling pathway and suppressed the protein expression of ERK1/2 and JNK1/2 in MAPKs signaling pathway in AIA-FLS. In addition, the protein expression of TNF-α, IL-17, RANKL, and iNOS was also found reduced. MU treatment significantly inhibited the mRNA expression of pro-inflammatory mediators (TNF-α, IL-1β, IL-6, MCP-1, IL-17, iNOS, and COX-2), transcription factors (NFкB-p65 and AP-1), and RANKL and attenuated the overproduction of TNF-α, IL-1β, IL-6, and MCP-1 (ELISA) in AIA-FLS. Furthermore, MU treatment significantly inhibited the level of lipid peroxidation, lysosomal enzymes release, and glycoproteins and increased antioxidant status (superoxide dismutase and catalase) in AIA-FLS. In conclusion, the results of this study provide evidence that MU possesses anti-inflammatory effect against AIA-FLS through the decrease in pro-inflammatory mediators expression by suppressing NFкB and MAPKs signaling pathways.

Keywords

Fibroblast-like synoviocytes Rheumatoid arthritis Majoon ushba NFкB Pro-inflammatory cytokines 

Notes

Acknowledgments

This work was supported by a Research Grant (Grant No. Z 28015/77/2013-HPC (EMR)-AYUSH-C) from the Central Council for Research in Unani Medicine, Dept of AYUSH, Ministry of Health and Family Welfare, Government of India, New Delhi.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Boissier MC, Semerano L, Challal S, Saidenberg KN, Falgarone G. Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction. J Autoimmun. 2012;39:222–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233:233–55.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Filer A. The fibroblast as a therapeutic target in rheumatoid arthritis. Curr Opin Pharmacol. 2013;13:413–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Nakano K, Okada Y, Saito K, Tanaka Y. Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblasts. Arthritis Rheum. 2004;50:2450–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang C, Yao H, Chen L, Jia J, Wang L, Dai J, et al. CD147 induces angiogenesis through a vascular endothelial growth factor and hypoxia-inducible transcription factor 1α-mediated pathway in rheumatoid arthritis. Arthritis Rheum. 2012;64:1818–27.CrossRefPubMedGoogle Scholar
  6. 6.
    Simmonds RE, Foxwell BM. Signalling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation. Rheumatology. 2008;47:584–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Thalhamer T, McGrath MA, Harnett MM. MAPKs and their relevance to arthritis and inflammation. Rheumatology. 2008;47:409–14.CrossRefPubMedGoogle Scholar
  8. 8.
    O’Shea JJ, Laurence A, McInnes IB. Back to the future: oral targeted therapy for RA and other autoimmune diseases. Nat Rev Rheumatol. 2013;9(3):173–82.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Quan L, Thiele GM, Tian J, Wang D. The development of novel therapies for rheumatoid arthritis. Expert Opin Ther Pat. 2008;18(7):723–38.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lone AH, Ahmad T, Naiyar AH. Clinical evaluation of efficacy of majoon ushba and roghane hindi in the management of psoriasis: a randomized single-blind, placebo-controlled study. J Ayurveda Integr Med. 2011;2:26–31.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ganesan R, Doss HM, Rasool M. Majoon ushba, a polyherbal compound ameliorates rheumatoid arthritis via regulating inflammatory and bone remodeling markers in rats. Cytokine. 2015;77:115–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Aggarwal BB, Prasad Sahdeo, Reuter S, Kannappan R, Yadev VR, et al. Identification of novel anti-inflammatory agents from ayurvedic medicine for prevention of chronic diseases: “reverse pharmacology” and “bedside to bench” approach. Curr Drug Targets. 2011;12:1595–653.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Murunikkara V, Pragasam SJ, Kodandaraman G, Sabina EP, Rasool M. Anti-inflammatory effect of piperine in adjuvant-induced arthritic rats—a biochemical approach. Inflammation. 2012;35:1348–56.CrossRefPubMedGoogle Scholar
  14. 14.
    Li R, Cai L, Tang W, Lei C, Hu C, Yu F. Apoptotic effect of geniposide on fibroblast-like synoviocytes in rats with adjuvant-induced arthritis via inhibiting erk signal pathway in vitro. Inflammation. 2015. doi: 10.1007/s10753-015-0219-9.Google Scholar
  15. 15.
    Chandrashekar KN, Muralidhara. d-Aspartic acid induced oxidative stress and mitochondrial dysfunctions in testis of prepubertal rats. Amino Acids. 2010;38:e817–27.CrossRefGoogle Scholar
  16. 16.
    Marklund S, Marklund G. Involvement of superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 1974;47:469–74.CrossRefPubMedGoogle Scholar
  17. 17.
    King J. The hydrolases-acid and alkaline phosphatases. In: Van D, editor. Practical clinical enzymology. London: Nostrand Company Limited; 1965. p. 191–208.Google Scholar
  18. 18.
    Vijayan V, Shyni GL, Helen A. Efficacy of Bacopa monniera (L.). Wettst in alleviating lysosomal instability in adjuvant-induced arthritis in rats. Inflammation. 2011;34:e630–8.CrossRefGoogle Scholar
  19. 19.
    Maruhn D. Rapid colorimetric assay of beta-galactosidase and N-acetyl-beta-glucosaminidase in human urine. Clin Chim Acta. 1976;73:453–61.CrossRefPubMedGoogle Scholar
  20. 20.
    Wagner WD. More sensitive assay discriminating galactosamine and glucosamine in mixtures. Anal Biochem. 1979;94:394–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Aminoff D. Methods for the quantitative estimation of N-acetyl neuraminic acid and their application to hydrolysates of sialomucoids. Biochem J. 1961;81:384–92.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Burger JA, Zvaifler NJ, Tsukada N, Firestein GS, Kipps TJ. Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1 and CD106 (VCAM-1)-dependent mechanism. J Clin Invest. 2001;107:305–15.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370(9602):1861–74.CrossRefPubMedGoogle Scholar
  24. 24.
    Komatsu N, Takayanagi H. Arthritogenic T cells in autoimmune arthritis. Int J Biochem Cell Biol. 2015;58:92–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Vervoordeldonk MJ, Tak PP. Cytokines in rheumatoid arthritis. Curr Rheumatol Rep. 2002;4(3):208–17.CrossRefPubMedGoogle Scholar
  26. 26.
    Bang JS, Oh DH, Choi HM, Sur BJ, Lim SJ, Kim JY, et al. Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1 beta-stimulated fibroblast-like synoviocytes and in rat arthritis models. Arthritis Res Ther. 2009;11:R49.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lee YA, Choi HM, Lee SH, Yang HI, Yoo MC, Hong SJ, et al. Synergy between adiponectin and interleukin-1β on the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in fibroblast-like synoviocytes. Exp Mol Med. 2012;44:440.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–88.CrossRefPubMedGoogle Scholar
  29. 29.
    Wei Z, Wang F, Song J, Lu Q, Zhao P, Xia Y, et al. Norisoboldine inhibits the production of interleukin-6 in fibroblast-like synoviocytes from adjuvant arthritis rats through PKC/MAPK/NF-κB-p65/CREB pathways. J Cell Biochem. 2012;113:2785–95.CrossRefPubMedGoogle Scholar
  30. 30.
    García-Vicuña R, Gómez-Gaviro MV, Domínguez-Luis MJ, Pec MK, González-Alvaro I, Alvaro-Gracia JM, et al. CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Rheum. 2004;50:3866–77.CrossRefPubMedGoogle Scholar
  31. 31.
    Ryu S, Lee JH, Kim SI. IL-17 increased the production of vascular endothelial growth factor in rheumatoid arthritis synoviocytes. Clin Rheumatol. 2005;25(1):16–20.CrossRefPubMedGoogle Scholar
  32. 32.
    Popko J, Marciniak J, Ilendo E, Knas M, Guszczyn T, Stasiak-Barmuta A, et al. Profile of exoglycosidases in synovial cell cultures derived from human synovial membrane. Cell Biochem Biophys. 2008;51:89–95.CrossRefPubMedGoogle Scholar
  33. 33.
    Zheng S, Zhong ZM, Qin S, Chen GX, Wu Q, Zeng JH, et al. Advanced oxidation protein products induce inflammatory response in fibroblast-like synoviocytes through nadph oxidase-dependent activation of NF-κB. Cell Physiol Biochem. 2013;32:972–85.CrossRefPubMedGoogle Scholar
  34. 34.
    Tanaka S, Matsui T, Murakami T, Ishizuka T, Sugiura M, Kawashima K, et al. Immunological abnormality associated with the augmented nitric oxide synthesis in adjuvant-induced arthritis. Int J Immunopharmacol. 1998;20:71–84.CrossRefPubMedGoogle Scholar
  35. 35.
    Wei X, Zhang X, Flick LM, Drissi H, Schwarz EM, O’Keefe RJ. Titanium particles stimulate COX-2 expression in synovial fibroblasts through an oxidative stress-induced, calpain-dependent, NF-B pathway. Am J Physiol Cell Physiol. 2009;297:C310–20.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Min SY, Hwang SY, Jung YO, Jeong J, Park SH, Cho CS, et al. Increase of cyclooxygenase-2 expression by interleukin 15 in rheumatoid synoviocytes. J Rheumatol. 2004;31:875–83.PubMedGoogle Scholar
  37. 37.
    Okazaki Y, Sawada T, Nagatani K, Komagata Y, Inoue T, Muto S, et al. Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis. J Rheumatol. 2005;32:1440–7.PubMedGoogle Scholar
  38. 38.
    Marotte H, Ruth JH, Campbell PL, Koch AE, Ahmed S. Green tea extract inhibits chemokine production, but up-regulates chemokine receptor expression, in rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis. Rheumatology. 2010;49:467–79.CrossRefPubMedGoogle Scholar
  39. 39.
    Agrawal M. Natural polyphenols based new therapeutic avenues for advanced biomedical applications. Drug Metab Rev. 2015;47:420–30.CrossRefPubMedGoogle Scholar
  40. 40.
    Khanna D, Sethi G, Ahn KS, Pandey MK, Kunnumakkara AB, Sung B, et al. Natural products as a gold mine for arthritis treatment. Curr Opin Pharmacol. 2007;7:344–51.CrossRefPubMedGoogle Scholar
  41. 41.
    Rahim AH, Setiawan B, Dewi FRP, Noor Z. Regulation by phloroglucinol of Nrf2/Maf-mediated expression of antioxidant enzymes and inhibition of osteoclastogenesis via the RANKL/RANK signaling pathway: in silico study. Acta Inform Med. 2015;23:228–32.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sanders M, Grundmann O. The use of glucosamine, devil’s claw (Harpagophytum procumbens), and acupuncture as complementary and alternative treatments for osteoarthritis. Altern Med Rev. 2011;16:228–38.PubMedGoogle Scholar
  43. 43.
    Moharregh-Khiabani D, Linker R, Gold R, Stangel M. Fumaric acid and its esters: an emerging treatment for multiple sclerosis. Curr Neuropharmacol. 2009;7:60–4.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Stahl W, Sies H. Antioxidant activity of carotenoids. Mol Aspects Med. 2003;24:345–51.CrossRefPubMedGoogle Scholar
  45. 45.
    Bin Sayeed MS, Ameen SS. Beta-sitosterol: a promising but orphan nutraceutical to fight against cancer. Nutr Cancer. 2015;67:1214–20.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ramamoorthi Ganesan
    • 1
  • Hari Madhuri Doss
    • 1
  • Mahaboobkhan Rasool
    • 1
    Email author
  1. 1.SMV 240, Immunopathology Lab, School of Bio Sciences and TechnologyVIT UniversityVelloreIndia

Personalised recommendations