Skip to main content
Erschienen in: Inflammation 3/2016

12.04.2016 | ORIGINAL ARTICLE

Shikonin Inhibits Inflammatory Cytokine Production in Human Periodontal Ligament Cells

verfasst von: Satoru Shindo, Yoshitaka Hosokawa, Ikuko Hosokawa, Kazumi Ozaki, Takashi Matsuo

Erschienen in: Inflammation | Ausgabe 3/2016

Einloggen, um Zugang zu erhalten

Abstract

Shikonin, which is derived from Lithospermum erythrorhizon, a herb used in traditional medicine, has long been considered to be a useful treatment for various diseases in traditional oriental medicine. Shikonin has recently been reported to have several pharmacological properties, e.g., it has anti-microbial, anti-tumor, and anti-inflammatory effects. The aim of this study was to examine whether shikonin is able to influence the production of interleukin (IL)-6, IL-8, and/or chemokine C-C motif ligand (CCL)20, which contribute to the pathogenesis of periodontal disease, in human periodontal ligament cells (HPDLC). The production levels of IL-6, IL-8, and CCL20 in HPDLC were determined using an ELISA. Western blot analysis was used to detect nuclear factor kappa B (NF-κB) pathway activation in HPDLC. Shikonin prevented IL-1β- or tumor necrosis factor (TNF)-α-mediated IL-6, IL-8, and CCL20 production in HPDLC. Moreover, we found that shikonin suppressed the phosphorylation and degradation of inhibitor of kappa B-alpha (IκB-α) in IL-1β- or TNF-α-stimulated HPDLC. These findings suggest that shikonin could have direct beneficial effects against periodontal disease by reducing IL-6, IL-8, and CCL20 production in periodontal lesions.
Literatur
1.
Zurück zum Zitat Teng, Y.T. 2003. The role of acquired immunity and periodontal disease progression. Critical Reviews in Oral Biology and Medicine 14: 237–252.CrossRefPubMed Teng, Y.T. 2003. The role of acquired immunity and periodontal disease progression. Critical Reviews in Oral Biology and Medicine 14: 237–252.CrossRefPubMed
2.
Zurück zum Zitat Taubman, M.A., P. Valverde, X. Han, and T. Kawai. 2005. Immune response: the key to bone resorption in periodontal disease. Journal of Periodontology 76: 2033–2041.CrossRefPubMed Taubman, M.A., P. Valverde, X. Han, and T. Kawai. 2005. Immune response: the key to bone resorption in periodontal disease. Journal of Periodontology 76: 2033–2041.CrossRefPubMed
3.
Zurück zum Zitat Graves, D. 2008. Cytokines that promote periodontal tissue destruction. Journal of Periodontology 79: 1585–1591.CrossRefPubMed Graves, D. 2008. Cytokines that promote periodontal tissue destruction. Journal of Periodontology 79: 1585–1591.CrossRefPubMed
4.
Zurück zum Zitat Garlet, G.P. 2010. Destructive and protective roles of cytokines in periodontitis: a re-appraisal from host defense and tissue destruction viewpoints. Journal of Dental Research 89: 1349–1363.CrossRefPubMed Garlet, G.P. 2010. Destructive and protective roles of cytokines in periodontitis: a re-appraisal from host defense and tissue destruction viewpoints. Journal of Dental Research 89: 1349–1363.CrossRefPubMed
5.
Zurück zum Zitat Papanicolaou, D.A., R.L. Wilder, S.C. Manolagas, and G.P. Chrousos. 1998. The pathophysiologic roles of interleukin-6 in human disease. Annals of Internal Medicine 128: 127–137.CrossRefPubMed Papanicolaou, D.A., R.L. Wilder, S.C. Manolagas, and G.P. Chrousos. 1998. The pathophysiologic roles of interleukin-6 in human disease. Annals of Internal Medicine 128: 127–137.CrossRefPubMed
6.
Zurück zum Zitat Ishihara, K., and T. Hirano. 2002. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine and Growth Factor Reviews 13: 357–368.CrossRefPubMed Ishihara, K., and T. Hirano. 2002. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine and Growth Factor Reviews 13: 357–368.CrossRefPubMed
7.
Zurück zum Zitat Baumann, H., and I. Kushner. 1998. Production of interleukin-6 by synovial fibroblasts in rheumatoid arthritis. American Journal of Pathology 152: 641–644.PubMedPubMedCentral Baumann, H., and I. Kushner. 1998. Production of interleukin-6 by synovial fibroblasts in rheumatoid arthritis. American Journal of Pathology 152: 641–644.PubMedPubMedCentral
8.
Zurück zum Zitat Kondo, A., T. Otsuka, R. Matsushima-Nishiwaki, G. Kuroyanagi, J. Mizutani, I. Wada, O. Kozawa, and H. Tokuda. 2013. Inhibition of SAPK/JNK leads to enhanced IL-1-induced IL-6 synthesis in osteoblasts. Archives of Biochemistry and Biophysics 535: 227–233.CrossRefPubMed Kondo, A., T. Otsuka, R. Matsushima-Nishiwaki, G. Kuroyanagi, J. Mizutani, I. Wada, O. Kozawa, and H. Tokuda. 2013. Inhibition of SAPK/JNK leads to enhanced IL-1-induced IL-6 synthesis in osteoblasts. Archives of Biochemistry and Biophysics 535: 227–233.CrossRefPubMed
9.
Zurück zum Zitat Hooper, W.C., D.J. Phillips, M.A. Renshaw, B.L. Evatt, and J.M. Benson. 1998. The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C. Journal of Immunology 161: 2567–2573. Hooper, W.C., D.J. Phillips, M.A. Renshaw, B.L. Evatt, and J.M. Benson. 1998. The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C. Journal of Immunology 161: 2567–2573.
10.
Zurück zum Zitat Naruishi, K., F. Nishimura, H. Yamada-Naruishi, K. Omori, M. Yamaguchi, and S. Takashiba. 2003. C-jun N-terminal kinase (JNK) inhibitor, SP600125, blocks interleukin (IL)-6-induced vascular endothelial growth factor (VEGF) production: cyclosporine A partially mimics this inhibitory effect. Transplantation 76: 1380–1382.CrossRefPubMed Naruishi, K., F. Nishimura, H. Yamada-Naruishi, K. Omori, M. Yamaguchi, and S. Takashiba. 2003. C-jun N-terminal kinase (JNK) inhibitor, SP600125, blocks interleukin (IL)-6-induced vascular endothelial growth factor (VEGF) production: cyclosporine A partially mimics this inhibitory effect. Transplantation 76: 1380–1382.CrossRefPubMed
11.
Zurück zum Zitat Yamaguchi, T., K. Naruishi, H. Arai, F. Nishimura, and S. Takashiba. 2008. IL-6/sIL-6R enhances cathepsin B and L production via caveolin-1-mediated JNK-AP-1 pathway in human gingival fibroblasts. Journal of Cellular Physiology 217: 423–432.CrossRefPubMed Yamaguchi, T., K. Naruishi, H. Arai, F. Nishimura, and S. Takashiba. 2008. IL-6/sIL-6R enhances cathepsin B and L production via caveolin-1-mediated JNK-AP-1 pathway in human gingival fibroblasts. Journal of Cellular Physiology 217: 423–432.CrossRefPubMed
12.
Zurück zum Zitat Hosokawa, Y., S. Shindo, I. Hosokawa, K. Ozaki, and T. Matsuo. 2014. IL-6 trans-signaling enhances CCL20 production from IL-1β-stimulated human periodontal ligament cells. Inflammation 37: 381–386.CrossRefPubMed Hosokawa, Y., S. Shindo, I. Hosokawa, K. Ozaki, and T. Matsuo. 2014. IL-6 trans-signaling enhances CCL20 production from IL-1β-stimulated human periodontal ligament cells. Inflammation 37: 381–386.CrossRefPubMed
13.
Zurück zum Zitat Gaffen, S.L., and G. Hajishengallis. 2008. A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. Journal of Dental Research 87: 817–828.CrossRefPubMedPubMedCentral Gaffen, S.L., and G. Hajishengallis. 2008. A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. Journal of Dental Research 87: 817–828.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Okamoto, K., and H. Takayanagi. 2011. Regulation of bone by the adaptive immune system in arthritis. International Immunopharmacology 11: 543–548.CrossRefPubMed Okamoto, K., and H. Takayanagi. 2011. Regulation of bone by the adaptive immune system in arthritis. International Immunopharmacology 11: 543–548.CrossRefPubMed
15.
Zurück zum Zitat Takashiba, S., M. Takigawa, K. Takahashi, F. Myokai, F. Nishimura, T. Chihara, H. Kurihara, Y. Nomura, and Y. Murayama. 1992. Interleukin-8 is a major neutrophil chemotactic factor derived from cultured human gingival fibroblasts stimulated with interleukin-1 beta or tumor necrosis factor alpha. Infection and Immunity 60: 5253–5258.PubMedPubMedCentral Takashiba, S., M. Takigawa, K. Takahashi, F. Myokai, F. Nishimura, T. Chihara, H. Kurihara, Y. Nomura, and Y. Murayama. 1992. Interleukin-8 is a major neutrophil chemotactic factor derived from cultured human gingival fibroblasts stimulated with interleukin-1 beta or tumor necrosis factor alpha. Infection and Immunity 60: 5253–5258.PubMedPubMedCentral
16.
Zurück zum Zitat Bickel, M. 1993. The role of interleukin-8 in inflammation and mechanisms of regulation. Journal of Periodontology 64: 456–460.PubMed Bickel, M. 1993. The role of interleukin-8 in inflammation and mechanisms of regulation. Journal of Periodontology 64: 456–460.PubMed
17.
Zurück zum Zitat Kantarci, A., K. Oyaizu, and T.E. Van Dyke. 2003. Neutrophil-mediated tissue injury in periodontal disease pathogenesis: findings from localized aggressive periodontitis. Journal of Periodontology 74: 66–75.CrossRefPubMed Kantarci, A., K. Oyaizu, and T.E. Van Dyke. 2003. Neutrophil-mediated tissue injury in periodontal disease pathogenesis: findings from localized aggressive periodontitis. Journal of Periodontology 74: 66–75.CrossRefPubMed
18.
Zurück zum Zitat Chen, X., L. Yang, J.J. Oppenheim, and M.Z. Howard. 2002. Cellular pharmacology studies of shikonin derivatives. Phytotherapy Research 16: 199–209.CrossRefPubMed Chen, X., L. Yang, J.J. Oppenheim, and M.Z. Howard. 2002. Cellular pharmacology studies of shikonin derivatives. Phytotherapy Research 16: 199–209.CrossRefPubMed
19.
Zurück zum Zitat Fu, Z., B. Deng, Y. Liao, L. Shan, F. Yin, Z. Wang, H. Zeng, D. Zuo, Y. Hua, and Z. Cai. 2013. The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis. BMC Cancer 13: 580.CrossRefPubMedPubMedCentral Fu, Z., B. Deng, Y. Liao, L. Shan, F. Yin, Z. Wang, H. Zeng, D. Zuo, Y. Hua, and Z. Cai. 2013. The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis. BMC Cancer 13: 580.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Kuo, H.M., T.C. Hsia, Y.C. Chuang, H.F. Lu, S.Y. Lin, and J.G. Chung. 2004. Shikonin inhibits the growth and N-acetylation of 2-aminofluorene in Helicobacter pylori from ulcer patients. Anticancer Research 24: 1587–1592.PubMed Kuo, H.M., T.C. Hsia, Y.C. Chuang, H.F. Lu, S.Y. Lin, and J.G. Chung. 2004. Shikonin inhibits the growth and N-acetylation of 2-aminofluorene in Helicobacter pylori from ulcer patients. Anticancer Research 24: 1587–1592.PubMed
21.
Zurück zum Zitat Liang, D., Y. Sun, Y. Shen, F. Li, X. Song, E. Zhou, F. Zhao, Z. Liu, Y. Fu, M. Guo, N. Zhang, Z. Yang, and Y. Cao. 2013. Shikonin exerts anti-inflammatory effects in a murine model of lipopolysaccharide-induced acute lung injury by inhibiting the nuclear factor-kappaB signaling pathway. International Immunopharmacology 16: 475–480.CrossRefPubMed Liang, D., Y. Sun, Y. Shen, F. Li, X. Song, E. Zhou, F. Zhao, Z. Liu, Y. Fu, M. Guo, N. Zhang, Z. Yang, and Y. Cao. 2013. Shikonin exerts anti-inflammatory effects in a murine model of lipopolysaccharide-induced acute lung injury by inhibiting the nuclear factor-kappaB signaling pathway. International Immunopharmacology 16: 475–480.CrossRefPubMed
22.
Zurück zum Zitat Long, P., J. Hu, N. Piesco, M. Buckley, and S. Agarwal. 2001. Low magnitude of tensile strain inhibits IL-1beta-dependent induction of pro-inflammatory cytokines and induces synthesis of IL-10 in human periodontal ligament cells in vitro. Journal of Dental Research 80: 1416–1420.CrossRefPubMed Long, P., J. Hu, N. Piesco, M. Buckley, and S. Agarwal. 2001. Low magnitude of tensile strain inhibits IL-1beta-dependent induction of pro-inflammatory cytokines and induces synthesis of IL-10 in human periodontal ligament cells in vitro. Journal of Dental Research 80: 1416–1420.CrossRefPubMed
23.
Zurück zum Zitat Okada, N., M. Kobayashi, K. Mugikura, Y. Okamatsu, S. Hanazawa, S. Kitano, and K. Hasegawa. 1997. Interleukin-6 production in human fibroblasts derived from periodontal tissues is differentially regulated by cytokines and a glucocorticoid. Journal of Periodontal Research 32: 559–569.CrossRefPubMed Okada, N., M. Kobayashi, K. Mugikura, Y. Okamatsu, S. Hanazawa, S. Kitano, and K. Hasegawa. 1997. Interleukin-6 production in human fibroblasts derived from periodontal tissues is differentially regulated by cytokines and a glucocorticoid. Journal of Periodontal Research 32: 559–569.CrossRefPubMed
24.
Zurück zum Zitat Lee, H.J., J.W. Cho, S.C. Kim, K.H. Kang, S.K. Lee, S.H. Pi, S.K. Lee, and E.C. Kim. 2006. Roles of p38 and ERK MAP kinases in IL-8 expression in TNF-alpha- and dexamethasone-stimulated human periodontal ligament cells. Cytokine 35: 67–76.CrossRefPubMed Lee, H.J., J.W. Cho, S.C. Kim, K.H. Kang, S.K. Lee, S.H. Pi, S.K. Lee, and E.C. Kim. 2006. Roles of p38 and ERK MAP kinases in IL-8 expression in TNF-alpha- and dexamethasone-stimulated human periodontal ligament cells. Cytokine 35: 67–76.CrossRefPubMed
25.
Zurück zum Zitat Zhu, L., Y. Wu, H. Wei, S. Yang, N. Zhan, X. Xing, and B. Peng. 2012. Up-regulation of IL-23 p19 expression in human periodontal ligament fibroblasts by IL-1β via concurrent activation of the NF-κB and MAPKs/AP-1 pathways. Cytokine 60: 171–178.CrossRefPubMed Zhu, L., Y. Wu, H. Wei, S. Yang, N. Zhan, X. Xing, and B. Peng. 2012. Up-regulation of IL-23 p19 expression in human periodontal ligament fibroblasts by IL-1β via concurrent activation of the NF-κB and MAPKs/AP-1 pathways. Cytokine 60: 171–178.CrossRefPubMed
26.
Zurück zum Zitat Bai, G.Z., H.T. Yu, Y.F. Ni, X.F. Li, Z.P. Zhang, K. Su, J. Lei, B.Y. Liu, C.K. Ke, D.X. Zhong, Y.J. Wang, and J.B. Zhao. 2013. Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice. Journal of Surgical Research 182: 303–311.CrossRefPubMed Bai, G.Z., H.T. Yu, Y.F. Ni, X.F. Li, Z.P. Zhang, K. Su, J. Lei, B.Y. Liu, C.K. Ke, D.X. Zhong, Y.J. Wang, and J.B. Zhao. 2013. Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice. Journal of Surgical Research 182: 303–311.CrossRefPubMed
27.
Zurück zum Zitat Xiong, J., J. Ni, G. Hu, J. Shen, Y. Zhao, L. Yang, J. Shen, G. Yin, C. Chen, G. Yu, Y. Hu, M. Xing, R. Wan, and X. Wang. 2013. Shikonin ameliorates cerulein-induced acute pancreatitis in mice. Journal of Ethnopharmacology 145: 573–580.CrossRefPubMed Xiong, J., J. Ni, G. Hu, J. Shen, Y. Zhao, L. Yang, J. Shen, G. Yin, C. Chen, G. Yu, Y. Hu, M. Xing, R. Wan, and X. Wang. 2013. Shikonin ameliorates cerulein-induced acute pancreatitis in mice. Journal of Ethnopharmacology 145: 573–580.CrossRefPubMed
28.
Zurück zum Zitat Yang, Y., J. Wang, Q. Yang, S. Wu, Z. Yang, H. Zhu, M. Zheng, W. Liu, W. Wu, J. He, and Z. Chen. 2014. Shikonin inhibits the lipopolysaccharide-induced release of HMGB1 in RAW264.7 cells via IFN and NF-κB signaling pathways. International Immunopharmacology 19: 81–87.CrossRefPubMed Yang, Y., J. Wang, Q. Yang, S. Wu, Z. Yang, H. Zhu, M. Zheng, W. Liu, W. Wu, J. He, and Z. Chen. 2014. Shikonin inhibits the lipopolysaccharide-induced release of HMGB1 in RAW264.7 cells via IFN and NF-κB signaling pathways. International Immunopharmacology 19: 81–87.CrossRefPubMed
29.
Zurück zum Zitat Min, R., Z. Zun, Y. Min, D. Wenhu, Y. Wenjun, and Z. Chenping. 2011. Shikonin inhibits tumor invasion via down-regulation of NF-κB-mediated MMP-9 expression in human ACC-M cells. Oral Diseases 17: 362–369.CrossRefPubMed Min, R., Z. Zun, Y. Min, D. Wenhu, Y. Wenjun, and Z. Chenping. 2011. Shikonin inhibits tumor invasion via down-regulation of NF-κB-mediated MMP-9 expression in human ACC-M cells. Oral Diseases 17: 362–369.CrossRefPubMed
30.
Zurück zum Zitat Huang, W.R., Y. Zhang, and X. Tang. 2014. Shikonin inhibits the proliferation of human lens epithelial cells by inducing apoptosis through ROS and caspase-dependent pathway. Molecules 19: 7785–7797.CrossRefPubMed Huang, W.R., Y. Zhang, and X. Tang. 2014. Shikonin inhibits the proliferation of human lens epithelial cells by inducing apoptosis through ROS and caspase-dependent pathway. Molecules 19: 7785–7797.CrossRefPubMed
31.
Zurück zum Zitat Chen, Y., L. Zheng, J. Liu, Z. Zhou, X. Cao, X. Lv, and F. Chen. 2014. Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways. International Immunopharmacology 21: 447–455.CrossRefPubMed Chen, Y., L. Zheng, J. Liu, Z. Zhou, X. Cao, X. Lv, and F. Chen. 2014. Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways. International Immunopharmacology 21: 447–455.CrossRefPubMed
Metadaten
Titel
Shikonin Inhibits Inflammatory Cytokine Production in Human Periodontal Ligament Cells
verfasst von
Satoru Shindo
Yoshitaka Hosokawa
Ikuko Hosokawa
Kazumi Ozaki
Takashi Matsuo
Publikationsdatum
12.04.2016
Verlag
Springer US
Erschienen in
Inflammation / Ausgabe 3/2016
Print ISSN: 0360-3997
Elektronische ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-016-0344-0

Weitere Artikel der Ausgabe 3/2016

Inflammation 3/2016 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.