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Inflammation

, Volume 39, Issue 1, pp 473–482 | Cite as

Rebamipide Suppresses Monosodium Urate Crystal-Induced Interleukin-1β Production Through Regulation of Oxidative Stress and Caspase-1 in THP-1 Cells

  • Seong-Kyu Kim
  • Jung-Yoon Choe
  • Ki-Yeun Park
Original Article

Abstract

This study investigated the effect of rebamipide on activation of the NLRP3 inflammasome and generation of reactive oxygen species (ROS) in monosodium urate (MSU) crystal-induced interleukin-1β (IL-1β) production. Human monocyte cell line THP-1 and human umbilical venous endothelial cells (HUVECs) were used to assess the inflammatory response to MSU crystals. NADP/NADPH activity assays were used as a marker of ROS generation. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to evaluate levels of IL-1β, caspase-1, NLRP3, associated speck-like protein (ASC), nuclear factor-κB (NF-κB), p65, IκBα, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). Experimental pharmaceuticals included rebamipide, colchicine, dexamethasone, and ascorbic acid. In THP-1 cells, treatment with MSU crystals increased NADP/NADPH ratios and IL-1β expression, and both of these responses were potently inhibited by addition of rebamipide. Rebamipide also attenuated enhanced expression of caspase-1 gene by MSU crystals (p < 0.05). Western blotting demonstrated that MSU crystals stimulated caspase-1 but not NLRP3 and ASC activation. Similarly, MSU crystals activated the NF-κB pathway, which in turn was blocked by rebamipide. Stimulation of HUVECs with MSU crystals increased expression of VCAM-1 and ICAM-1, which were markedly inhibited by both rebamipide and dexamethasone. This study demonstrated that rebamipide inhibits IL-1β activation through suppression of ROS-mediated NF-κB signaling pathways and caspase-1 activation in MSU crystal-induced inflammation.

KEY WORDS

uric acid interleukin-1β inflammasome inflammation rebamipide 

Notes

Acknowledgments

This work was supported by a grant from the Research Institute of Medical Science, Catholic University of Daegu (2015).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest concerning this article.

References

  1. 1.
    Choi, H.K., D.B. Mount, and A.M. Reginato. 2005. Pathogenesis of gout. Annals of Internal Medecine 143: 499–516.CrossRefGoogle Scholar
  2. 2.
    Martinon, F. 2010. Mechanisms of uric acid crystal-mediated autoinflammation. Immunology 233: 218–232.CrossRefGoogle Scholar
  3. 3.
    Shi, Y., J.E. Evans, and K.L. Rock. 2003. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425: 516–521.CrossRefPubMedGoogle Scholar
  4. 4.
    Martinon, F., V. Petrilli, A. Mayor, A. Tardivel, and J. Tschopp. 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440: 237–241.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhou, R., A.S. Yazdi, P. Menu, and J. Tschopp. 2011. A role for mitochondria in NLRP3 inflammasome activation. Nature 469: 221–225.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhou, R., A. Tardivel, B. Thorens, I. Choi, and J. Tschopp. 2010. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature Immunology 11: 136–140.CrossRefPubMedGoogle Scholar
  7. 7.
    Arakawa, T., K. Kobayashi, T. Yoshikawa, and A. Tarnawski. 1998. Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Digestive Diseases and Sciences 43: 5S–13S.PubMedGoogle Scholar
  8. 8.
    Kim, H., J.Y. Seo, and K.H. Kim. 2000. Inhibition of lipid peroxidation, NF-κB activation and IL-8 production by rebamipide in Helicobacter pylori-stimulated gastric epithelial cells. Digestive Diseases and Sciences 45: 621–628.CrossRefPubMedGoogle Scholar
  9. 9.
    Farhadi, A., A. Keshavarzian, L.R. Fitzpatrick, E. Mutlu, Y. Zhang, and A. Banan. 2002. Modulatory effects of plasma and colonic milieu of patients with ulcerative colitis on neutrophil reactive oxygen species production in presence of a novel antioxidant, rebamipide. Digestive Diseases and Sciences 47: 1342–1348.CrossRefPubMedGoogle Scholar
  10. 10.
    Choe, J.Y., H.Y. Jung, K.Y. Park, and S.K. Kim. 2014. Enhanced p62 expression through impaired proteasomal degradation is involved in caspase-1 activation in monosodium urate crystal-induced interleukin-1β expression. Rheumatology (Oxford) 53: 1043–1053.CrossRefGoogle Scholar
  11. 11.
    Paravicini, T.M., and R.M. Touyz. 2008. NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care 31: S170–S180.CrossRefPubMedGoogle Scholar
  12. 12.
    Moon, S.J., Y.J. Woo, J.H. Woo, M.K. Park, H.J. Oh, J.S. Park, E.K. Kim, M.L. Cho, S.H. Park, H.Y. Kim, and J.K. Min. 2012. Rebamipide attenuates pain severity and cartilage degeneration in a rat model of osteoarthritis by downregulating oxidative damage and catabolic activity in chondrocytes. Osteoarthritis and Cartilage 20: 1426–1438.CrossRefPubMedGoogle Scholar
  13. 13.
    Kohashi, M., N. Ishimaru, R. Arakaki, and Y. Hayashi. 2008. Effective treatment with oral administration of rebamipide in a mouse model of Sjögren’s syndrome. Arthritis and Rheumatism 58: 389–400.CrossRefPubMedGoogle Scholar
  14. 14.
    Sugai, S., H. Takahashi, S. Ohta, M. Nishinarita, M. Takei, S. Sawada, K. Yamaji, H. Oka, H. Umehara, I. Koni, E. Sugiyama, S. Nishiyama, and A. Kawakami. 2009. Efficacy and safety of rebamipide for the treatment of dry mouth symptoms in patients with Sjögren’s syndrome: a double-blind placebo-controlled multicenter trial. Modern Rheumatology 19: 114–124.CrossRefPubMedGoogle Scholar
  15. 15.
    Bang, D., B. Choi, H.J. Kwon, E.S. Lee, S. Lee, and S. Sohn. 2008. Rebamipide affects the efficiency of colchicine for the herpes simplex virus-induced inflammation in a Behcet’s disease mouse model. European Journal of Pharmacology 598: 112–117.CrossRefPubMedGoogle Scholar
  16. 16.
    Jhang, J.J., Y.T. Cheng, C.Y. Ho, and G.C. Yen. 2014. Monosodium urate crystals trigger Nrf2- and heme oxygenase-1-dependent inflammation in THP-1 cells. Cellular & Molecular Immunology 12(4): 424–434.CrossRefGoogle Scholar
  17. 17.
    Choe, J.Y., K.Y. Park, and S.K. Kim. 2015. Oxidative stress by monosodium urate crystals promotes renal cell apoptosis through mitochondrial caspase-dependent pathway in human embryonic kidney 293 cells: mechanism for urate-induced nephropathy. Apoptosis 20: 38–49.CrossRefPubMedGoogle Scholar
  18. 18.
    Forman, H.J., and M. Torres. 2002. Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. American Journal of Respiratory and Critical Care Medicine 166: S4–S8.CrossRefPubMedGoogle Scholar
  19. 19.
    Sautin, Y.Y., T. Nakagawa, S. Zharikov, and R.J. Johnson. 2007. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. American Journal of Respiratory and Critical Care Medicine 293: C584–C596.Google Scholar
  20. 20.
    Kostura, M.J., M.J. Tocci, G. Limjuco, J. Chin, P. Cameron, A.G. Hillman, N.A. Chartrain, and J.A. Schmidt. 1989. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proceedings of the National Academy of Sciences of the United States of America 86: 5227–5231.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Black, R.A., S.R. Kronheim, and P.R. Sleath. 1989. Activation of interleukin-1 beta by a co-induced protease. FEBS Letters 247: 386–390.CrossRefPubMedGoogle Scholar
  22. 22.
    Busso, N., and A. So. 2010. Mechanisms of inflammation in gout. Arthritis Research & Therapy 12: 206.CrossRefGoogle Scholar
  23. 23.
    Jaramillo, M., M. Godbout, P.H. Naccache, and M. Olivier. 2004. Signaling events involved in macrophage chemokine expression in response to monosodium urate crystals. The Journal of Biological Chemistry 279: 52797–52805.CrossRefPubMedGoogle Scholar
  24. 24.
    Liu-Bryan, R., K. Pritzker, G.S. Firestein, and R. Terkeltaub. 2005. TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. Journal of Immunology 174: 5016–5023.CrossRefGoogle Scholar
  25. 25.
    Hiscott, J., J. Marois, J. Garoufalis, M. D'Addario, A. Roulston, I. Kwan, N. Pepin, J. Lacoste, H. Nguyen, G. Bensi, and M. Fenton. 1993. Characterization of a functional NF-κB site in the human interleukin 1β promoter: evidence for a positive autoregulatory loop. Molecular and Cellular Biology 13: 6231–6240.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Desaulniers, P., M. Fernandes, C. Gilbert, S.G. Bourgoin, and P.H. Naccache. 2001. Crystal-induced neutrophil activation. VII. Involvement of Syk in the responses to monosodium urate crystals. Journal of Leukocyte Biology 70: 659–668.PubMedGoogle Scholar
  27. 27.
    Choe, J.Y., K.Y. Park, S.J. Lee, S.H. Park, and S.K. Kim. 2010. Rebamipide inhibits tumor necrosis factor-α-induced interleukin-8 expression by suppressing the NF-κB signal pathway in human umbilical vein endothelial cells. Inflammation Research 59: 1019–1026.CrossRefPubMedGoogle Scholar
  28. 28.
    Terkeltaub, R., C. Zachariae, D. Santoro, J. Martin, P. Peveri, and K. Matsushima. 1991. Monocyte-derived neutrophil chemotactic factor/interleukin-8 is a potential mediator of crystal-induced inflammation. Arthritis and Rheumatism 34: 894–903.CrossRefPubMedGoogle Scholar
  29. 29.
    So, A., T. De Smedt, S. Revaz, and J. Tschopp. 2007. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Research & Therapy 9: R28.CrossRefGoogle Scholar
  30. 30.
    Cronstein, B.N., Y. Molad, J. Reibman, E. Balakhane, R.I. Levin, and G. Weissmann. 1995. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. Journal of Clinical Investigation 96: 994–1002.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Greenbaum, D., C. Colangelo, K. Williams, and M. Gerstein. 2003. Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biology 4: 117.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Bevilacqua, M.P. 1993. Endothelial-leukocyte adhesion molecules. Annual Review of Immunology 11: 767–804.CrossRefPubMedGoogle Scholar
  33. 33.
    Reinhardt, P.H., P.H. Naccache, P.E. Poubelle, R. De Médicis, M.E. Kehrli Jr., and P. Kubes. 1996. Monosodium urate crystals promote neutrophil adhesion via a CD18-independent and selectin-independent mechanism. American Journal of Physiology 270: C31–C39.PubMedGoogle Scholar
  34. 34.
    Chapman, P.T., F. Jamar, A.A. Harrison, R.M. Binns, A.M. Peters, and D.O. Haskard. 1994. Noninvasive imaging of E-selectin expression by activated endothelium in urate crystal-induced arthritis. Arthritis and Rheumatism 37: 1752–1756.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of Internal Medicine, School of MedicineCatholic University of DaeguDaeguRepublic of Korea
  2. 2.Arthritis and Autoimmunity Research CenterCatholic University of DaeguDaeguRepublic of Korea

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