Skip to main content

Thymoquinone Inhibits IL-1β-Induced Inflammation in Human Osteoarthritis Chondrocytes by Suppressing NF-κB and MAPKs Signaling Pathway

Abstract

Thymoquinone, an active ingredient isolated from Nigella sativa, has been reported to have anti-inflammatory effects. However, the anti-inflammatory effect of thymoquinone on IL-1β-stimulated osteoarthritis chondrocytes remains unclear. In this study, we designed to investigate the anti-inflammatory effects and elucidated the underlying mechanism of thymoquinone on IL-1β-stimulated human osteoarthritis chondrocytes. The effects of thymoquinone on inflammatory mediators COX-2, iNOS, NO, PGE2, as well as MMP-1, MMP3, MMP13 production were detected. The results demonstrated that thymoquinone concentration-dependently inhibited IL-1β-induced COX-2, iNOS, NO, and PGE2 production. Thymoquinone also suppressed IL-1β-induced MMP-1, MMP3, and MMP13 production. We found that thymoquinone significantly inhibited IL-1β-induced NF-κB activation and IκBα degradation. In addition, thymoquinone was found to suppress IL-1β-induced mitogen-activated protein kinases (MAPKs) activation. In conclusion, thymoquinone inhibited IL-1β-induced inflammatory mediator production by inhibition of NF-κB and MAPKs signaling pathways in osteoarthritis chondrocytes. Thymoquinone may be a potential agent in the treatment of osteoarthritis.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Moe, R.H., T. Uhlig, I. Kjeken, K.B. Hagen, T.K. Kvien, and M. Grotle. 2010. Multidisciplinary and multifaceted outpatient management of patients with osteoarthritis: protocol for a randomised, controlled trial. BMC Musculoskeletal Disorders 11: 253.

    PubMed Central  Article  PubMed  Google Scholar 

  2. 2.

    Helmick, C.G., D.T. Felson, R.C. Lawrence, S. Gabriel, R. Hirsch, C.K. Kwoh, M.H. Liang, H.M. Kremers, M.D. Mayes, P.A. Merkel, et al. 2008. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis and Rheumatism 58: 15–25.

    Article  PubMed  Google Scholar 

  3. 3.

    Melchiorri, C., R. Meliconi, L. Frizziero, T. Silvestri, L. Pulsatelli, I. Mazzetti, R.M. Borzi, M. Uguccioni, and A. Facchini. 1998. Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis and Rheumatism 41: 2165–2174.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Fernandes, J.C., J. Martel-Pelletier, and J.P. Pelletier. 2002. The role of cytokines in osteoarthritis pathophysiology. Biorheology 39: 237–246.

    CAS  PubMed  Google Scholar 

  5. 5.

    Honorati, M.C., L. Cattini, and A. Facchini. 2004. IL-17, IL-1beta and TNF-alpha stimulate VEGF production by dedifferentiated chondrocytes. Osteoarthritis and Cartilage 12: 683–691.

    Article  PubMed  Google Scholar 

  6. 6.

    Lianxu, C., J. Hongti, and Y. Changlong. 2006. NF-kappaBp65-specific siRNA inhibits expression of genes of COX-2, NOS-2 and MMP-9 in rat IL-1beta-induced and TNF-alpha-induced chondrocytes. Osteoarthritis and Cartilage 14: 367–376.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Tetlow, L.C., D.J. Adlam, and D.E. Woolley. 2001. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis and Rheumatism 44: 585–594.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Chowdhury, T.T., D.L. Bader, and D.A. Lee. 2001. Dynamic compression inhibits the synthesis of nitric oxide and PGE(2) by IL-1beta-stimulated chondrocytes cultured in agarose constructs. Biochemical and Biophysical Research Communications 285: 1168–1174.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Vergnolle, N., J.L. Wallace, N.W. Bunnett, and M.D. Hollenberg. 2001. Protease-activated receptors in inflammation, neuronal signaling and pain. Trends in Pharmacological Sciences 22: 146–152.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Moon, D.O., M.O. Kim, Y.H. Choi, Y.M. Park, and G.Y. Kim. 2010. Curcumin attenuates inflammatory response in IL-1beta-induced human synovial fibroblasts and collagen-induced arthritis in mouse model. International Immunopharmacology 10: 605–610.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Abu-Dahab, R., F. Odeh, S.I. Ismail, H. Azzam, and A. Al Bawab. 2013. Preparation, characterization and antiproliferative activity of thymoquinone-beta-cyclodextrin self assembling nanoparticles. Pharmazie 68: 939–944.

    CAS  PubMed  Google Scholar 

  12. 12.

    Galaly, S.R., O.M. Ahmed, and A.M. Mahmoud. 2014. Thymoquinone and curcumin prevent gentamicin-induced liver injury by attenuating oxidative stress, inflammation and apoptosis. Journal of Physiology and Pharmacology 65: 823–832.

    CAS  PubMed  Google Scholar 

  13. 13.

    Khalife, R., H. el Stephany, O. Tarras, M.H. Hodroj, and S. Rizk. 2014. Antiproliferative and proapoptotic effects of topotecan in combination with thymoquinone on acute myelogenous leukemia. Clinical Lymphoma, Myeloma & Leukemia 14(Suppl): S46–S55.

    Article  Google Scholar 

  14. 14.

    Hosseini, M., S. Zakeri, S. Khoshdast, F.T. Yousefian, M. Rastegar, F. Vafaee, S. Kahdouee, F. Ghorbani, H. Rakhshandeh, and S.A. Kazemi. 2012. The effects of Nigella sativa hydro-alcoholic extract and thymoquinone on lipopolysaccharide - induced depression like behavior in rats. Journal of Pharmacology Bioallied Science 4: 219–225.

    Article  Google Scholar 

  15. 15.

    Alkharfy, K.M., N.M. Al-Daghri, O.S. Al-Attas, and M.S. Alokail. 2011. The protective effect of thymoquinone against sepsis syndrome morbidity and mortality in mice. International Immunopharmacology 11: 250–254.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Cheng, A.W., T.V. Stabler, M. Bolognesi, and V.B. Kraus. 2011. Selenomethionine inhibits IL-1beta inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) expression in primary human chondrocytes. Osteoarthritis and Cartilage 19: 118–125.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  17. 17.

    Sandell, L.J., X. Xing, C. Franz, S. Davies, L.W. Chang, and D. Patra. 2008. Exuberant expression of chemokine genes by adult human articular chondrocytes in response to IL-1beta. Osteoarthritis and Cartilage 16: 1560–1571.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  18. 18.

    Towle, C.A., H.H. Hung, L.J. Bonassar, B.V. Treadwell, and D.C. Mangham. 1997. Detection of interleukin-1 in the cartilage of patients with osteoarthritis: a possible autocrine/paracrine role in pathogenesis. Osteoarthritis and Cartilage 5: 293–300.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Chowdhury, T.T., D.L. Bader, and D.A. Lee. 2006. Dynamic compression counteracts IL-1beta induced iNOS and COX-2 activity by human chondrocytes cultured in agarose constructs. Biorheology 43: 413–429.

    PubMed  Google Scholar 

  20. 20.

    Woodell-May, J., A. Matuska, M. Oyster, Z. Welch, K. O'Shaughnessey, and J. Hoeppner. 2011. Autologous protein solution inhibits MMP-13 production by IL-1beta and TNFalpha-stimulated human articular chondrocytes. Journal of Orthopaedic Research 29: 1320–1326.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Aida, Y., M. Maeno, N. Suzuki, H. Shiratsuchi, M. Motohashi, and H. Matsumura. 2005. The effect of IL-1beta on the expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human chondrocytes. Life Sciences 77: 3210–3221.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Ghosh, S., M.J. May, and E.B. Kopp. 1998. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annual Review of Immunology 16: 225–260.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Lawrence, T., M. Bebien, G.Y. Liu, V. Nizet, and M. Karin. 2005. IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 434: 1138–1143.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Tak, P.P., and G.S. Firestein. 2001. NF-kappaB: a key role in inflammatory diseases. Journal of Clinical Investigation 107: 7–11.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  25. 25.

    De Martin, R., M. Hoeth, R. Hofer-Warbinek, and J.A. Schmid. 2000. The transcription factor NF-kappa B and the regulation of vascular cell function. Arteriosclerosis, Thrombosis, and Vascular Biology 20: E83–E88.

    Article  PubMed  Google Scholar 

  26. 26.

    Ghosh, M., V. Aguirre, K. Wai, H. Felfly, W.D. Dietrich, and D.D. Pearse. 2015. The Interplay between Cyclic AMP, MAPK, and NF-kappa B pathways in response to proinflammatory signals in microglia. Biomedical Research International 2015: 308461.

    Article  Google Scholar 

Download references

Conflict of Interest

The authors have no conflict of interest to declare.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Dehong Guan.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, D., Qiao, J., Zhao, X. et al. Thymoquinone Inhibits IL-1β-Induced Inflammation in Human Osteoarthritis Chondrocytes by Suppressing NF-κB and MAPKs Signaling Pathway. Inflammation 38, 2235–2241 (2015). https://doi.org/10.1007/s10753-015-0206-1

Download citation

KEY WORDS

  • thymoquinone
  • osteoarthritis chondrocyte
  • IL-1β
  • NF-κB