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Cepharanthine Inhibits IFN-γ-Induced CXCL10 by Suppressing the JAK2/STAT1 Signal Pathway in Human Salivary Gland Ductal Cells

Inflammation volume 41, pages 50–58 (2018)Cite this article

Abstract

Cepharanthine, a biscolaurine alkaloid isolated from the plant Stephania cephalantha Hayata, has been reported to have potent anti-inflammatory properties. Here, we investigated the effects of cepharanthine on the expression of CXCL10 (a CXC chemokine induced by interferon-gamma [IFN-γ] that has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions) in IFN-γ-treated human salivary gland cell lines. We observed that IFN-γ-induced CXCL10 production in NS-SV-DC cells (a human salivary gland ductal cell line), but not in NS-SV-AC cells (a human salivary gland acinar cell line). Cepharanthine inhibited the IFN-γ-induced CXCL10 production in NS-SV-DC cells. A Western blot analysis showed that cepharanthine prevented the phosphorylation of JAK2 and STAT1, but did not interfere with the NF-κB pathway. Moreover, cepharanthine inhibited the IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggest that cepharanthine suppresses IFN-γ-induced CXCL10 production via the inhibition of the JAK2/STAT1 signaling pathway in human salivary gland ductal cells. Our findings also indicate that cepharanthine could inhibit the chemotaxis of Jurkat T cells by reducing CXCL10 production.

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References

  1. Alspaugh, M.A., and K. Whaley. 1981. In Sjögren’s syndrome, textbook of Rheumatology, ed. W.N. Kelley, E.D. Harris, S. Ruddy, and C.B. Sledge, 971–999. Philadelphia: W.B. Saunders.

    Google Scholar 

  2. Daniels, T.E. 1984. Labial salivary gland biopsy in Sjögren's syndrome: Assessment as a diagnostic criterion in 362 suspected cases. Arthritis and Rheumatism 27: 147–156.

    CAS  Article  PubMed  Google Scholar 

  3. Hamano, H., I. Saito, N. Haneji, Y. Mitsuhashi, and Hayashi Y. MiyasakaN. 1993. Expressions of cytokine genes during development of autoimmune sialadenitis in MRL/lpr mice. European Journal of Immunology 23: 2387–2391.

    CAS  Article  PubMed  Google Scholar 

  4. Fox, R.I., H.I. Kang, D. Ando, J. Abrams, and E. Pisa. 1994. Cytokine mRNA expression in salivary gland biopsies of Sjögren's syndrome. Journal of Immunology 152: 5532–5529.

    CAS  Google Scholar 

  5. Li, H., J.A. Ice, C.J. Lessard, and K.L. Sivils. 2013. Interferons in Sjögren’s syndrome: genes, mechanisms, and effects. Frontiers in Immunology 20 (4): 290. https://doi.org/10.3389/fimmu.2013.00290.

    Google Scholar 

  6. Hall, J.C., A.N. Baer, A.A. Shah, L.A. Criswell, C.H. Shiboski, A. Rosen, and L. Casciola-Rosen. 2015. Molecular subsetting of interferon pathways in Sjögren's syndrome. Arthritis & Rhematology 67: 2437–2446.

    CAS  Article  Google Scholar 

  7. Nocturne, G., and X. Mariette. 2013. Advances in understanding the pathogenesis of primary Sjögren’s syndrome. Nature Reviews. Rheumatology 9: 544–556.

    CAS  Article  PubMed  Google Scholar 

  8. Luster, A.D., J.C. Unkeless, and J.V. Ravetch. 1985. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature 315: 672–676.

    CAS  Article  PubMed  Google Scholar 

  9. García-López, M.A., F. Sánchez-Madrid, J.M. Rodríguez-Frade, M. Mellado, A. Acevedo, M.I. García, J.P. Albar, C. Martínez, and M. Marazuela. 2001. CXCR3 chemokine receptor distribution in normal and inflamed tissues: Expression on activated lymphocytes, endothelial cells, and dendritic cells. Laboratory Investigation 81: 409–418.

    Article  PubMed  Google Scholar 

  10. Groom, J.R., and A.D. Luster. 2011. CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunology and Cell Biology 89: 207–215.

    CAS  Article  PubMed  Google Scholar 

  11. Hartl, D., S. Krauss-Etschmann, B. Koller, P.L. Hordijk, T.W. Kuijpers, F. Hoffmann, A. Hector, E. Eber, V. Marcos, I. Bittmann, O. Eickelberg, M. Griese, and D. Roos. 2008. Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. Journal of Immunology 181: 8053–8067.

    CAS  Article  Google Scholar 

  12. Tomita, K., B.L. Freeman, S.F. Bronk, N.K. LeBrasseur, T.A. White, P. Hirsova, and S.H. Ibrahim. 2016. CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Scientific Reports 6: 28786.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Ogawa, N., L. Ping, L. Zhenjun, Y. Takada, and S. Sugai. 2002. Involvement of the interferon-γ-induced T cell-attracting chemokines, interferon-γ-inducible 10-kD protein (CXCL10) and monokine induced by interferon-γ (CXCL9), in the salivary gland lesions of patients with Sjögren's syndrome. Arthritis and Rheumatism 46: 2730–2741.

    CAS  Article  PubMed  Google Scholar 

  14. Ogawa, N., T. Kawanami, K. Shimoyama, L. Ping, and S. Sugai. 2004. Expression of interferon-inducible T cell alpha chemoattractant (CXCL11) in the salivary glands of patients with Sjögren’s syndrome. Clinical Immunology 112: 235–238.

    CAS  Article  PubMed  Google Scholar 

  15. Hasegawa, H., A. Inoue, M. Kohno, M. Muraoka, T. Miyazaki, M. Terada, T. Nakayama, O. Yoshie, M. Nose, and M. Yasukawa. 2006. Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice. Arthritis and Rheumatism 54: 1174–1183.

    CAS  Article  PubMed  Google Scholar 

  16. Gutterman, J.U., S. Fine, J. Quesada, S.J. Horning, J.F. Levine, R. Alexanian, L. Bernhardt, M. Kramer, H. Spiegel, W. Colburn, P. Trown, T. Merigan, and Z. Dziewanowski. 1982. Recombinant leukocyte A interferon: Pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Annals of Internal Medicine 96: 549–556.

    CAS  Article  PubMed  Google Scholar 

  17. Ono, M. 1987. Antitumor effect of cepharanthine: activation of regional lymph node lymphocytes by intratumoral administration. Clinical Immunology 19: 1061–1064.

    Google Scholar 

  18. Morioka, S., M. Ono, N. Tanaka, and K. Orita. 1985. Synergistic activation of rat alveolar macrophages by cepharanthine and OK-432. Gan to Kagaku Ryoho 12: 1470–1475.

    CAS  PubMed  Google Scholar 

  19. Azuma, M., K. Aota, T. Tamatani, K. Motegi, T. Yamashita, Y. Ashida, Y. Hayashi, and M. Sato. 2002. Suppression of tumor necrosis factor α-induced matrix metalloproteinase 9 production in human salivary gland acinar cells by cepharanthine occurs via down-regulation of nuclear factor κB: A possible therapeutic agent for preventing the destruction of the acinar structure in the salivary glands of Sjögren's syndrome patients. Arthritis and Rheumatism 46: 1585–1594.

    CAS  Article  PubMed  Google Scholar 

  20. Azuma, M., Y. Ashida, T. Tamatani, K. Motegi, N. Takamaru, N. Ishimaru, Y. Hayashi, and M. Sato. 2006. Cepharanthin, a biscoclaurine alkaloid, prevents destruction of acinar tissues in murine Sjögren’s syndrome. The Journal of Rheumatology 33: 912–920.

    CAS  PubMed  Google Scholar 

  21. Yamanoi, T., K. Aota, Y. Momota, and M. Azuma. 2017. Treatment with the biscoclaurine alkaloid cepharanthin for improved salivary secretion in primary Sjögren's syndrome patients. Journal of Oral Health Biosciences 29: 39–48.

    Google Scholar 

  22. Azuma, M., T. Tamatani, Y. Kasai, and M. Sato. 1993. Immortalization of normal human salivary gland cells with duct-, myoepithelial-, acinar-, or squamous phenotype by transfection of SV40 ori-mutant DNA. Laboratory Investigation 69: 24–42.

    CAS  PubMed  Google Scholar 

  23. Hogan, J.C., and J.M. Stephens. 2001. The identification and characterization of a STAT 1 binding site in the PPARγ2 promoter. Biochemical and Biophysical Research Communications 287: 484–492.

    CAS  Article  PubMed  Google Scholar 

  24. Majumder, S., L.Z. Zhou, P. Chaturvedi, G. Babcock, S. Aras, and R.M. Ransohoff. 1998. p48/STAT-1alpha-containing complexes play a predominant role in induction of IFN-gamma-inducible protein, 10 kDa (IP-10) by IFN-gamma alone or in synergy with TNF-alpha. Journal of Immunology 161: 4736–4744.

    CAS  Google Scholar 

  25. Azuma, M., K. Motegi, K. Aota, Y. Hayashi, and M. Sato. 1997. Role of cytokines in the destruction of acinar structure in Sjögren’s syndrome salivary glands. Laboratory Investigation 77: 269–280.

    CAS  PubMed  Google Scholar 

  26. Hall, J.C., L. Casciola-Rosen, A.E. Berger, E.K. Kapsogeorgou, C. Cheadle, A.G. Tzioufas, A.N. Baer, and A. Rosen. 2012. Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proceedings of the National Academy of Sciences of the United States of America 109: 17609–17614.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Lacotte, S., S. Brun, S. Muller, and H. Dumortier. 2009. CXCR3, inflammation, and autoimmune diseases. Annals of the New York Academy of Sciences 1173: 310–317.

    CAS  Article  PubMed  Google Scholar 

  28. Gangur, V., F.E. Simons, and K.T. Hayglass. 1998. Human IP-10 selectively promotes dominance of polyclonally activated and environmental antigen-driven IFN-gamma over IL-4 responses. The FASEB Journal 12: 705–713.

    CAS  PubMed  Google Scholar 

  29. Qi, X.F., D.H. Kim, Y.S. Yoon, D. Jin, X.Z. Huang, J.H. Li, Y.K. Deung, and K.J. Lee. 2009. Essential involvement of cross-talk between IFN-γ and TNF-α in CXCL10 production in human THP-1 monocytes. Journal of Cellular Physiology 220: 690–697.

    CAS  Article  PubMed  Google Scholar 

  30. Kelner, G.S., J. Kennedy, K.B. Bacon, S. Kleyensteuber, D.A. Largaespada, N.A. Jenkins, N.G. Copeland, J.F. Bazan, K.W. Moore, T.J. Schall, et al. 1994. Lymphotactin: A cytokine that represents a new class of chemokine. Science 266: 1395–1399.

    CAS  Article  PubMed  Google Scholar 

  31. Murdoch, C., and A. Finn. 2000. Chemokine receptors and their role in inflammation and infectious diseases. Blood 95: 3032–3043.

    CAS  PubMed  Google Scholar 

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Financial Support

This work was supported by Grant-in-Aid for Scientific Research from the Japan Ministry of Education, Culture, Sports, Science and Technology (No. 15K11254).

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  1. Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan

    Keiko Aota, Tomoko Yamanoi, Koichi Kani & Masayuki Azuma

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  1. Keiko Aota
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  2. Tomoko Yamanoi
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Correspondence to Keiko Aota.

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Aota, K., Yamanoi, T., Kani, K. et al. Cepharanthine Inhibits IFN-γ-Induced CXCL10 by Suppressing the JAK2/STAT1 Signal Pathway in Human Salivary Gland Ductal Cells. Inflammation 41, 50–58 (2018). https://doi.org/10.1007/s10753-017-0662-x

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  • DOI: https://doi.org/10.1007/s10753-017-0662-x

KEY WORDS

  • cepharanthine
  • CXCL10
  • IFN-γ
  • JAK/STAT1 signaling
  • salivary gland ductal cells
  • primary Sjögren’s syndrome