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1,6-O,O-Diacetylbritannilactone Inhibits Eotaxin-1 and ALOX15 Expression Through Inactivation of STAT6 in A549 Cells

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Abstract

1,6-O,O-Diacetylbritannilactone (OODBL), a plant sesquiterpene lactone, was previously reported to show multiple pharmacological effects such as anti-cancer and anti-inflammatory activities. In this study, we investigated the anti-inflammatory effect of OODBL on interleukin (IL)-4-induced signal transducer and activator of transcription 6 (STAT6) signaling pathway in human lung A549 cells. We found that OODBL dramatically inhibited IL-4-induced messenger RNA (mRNA) expression of eotaxin-1 and arachidonate 15-lipoxygenase-1 (ALOX15) in a dose-dependent manner. To clarify the action mechanism of OODBL, we examined the effect of OODBL on activation of STAT6. OODBL decreased both STAT6 phosphorylation and reporter gene activity. Furthermore, OODBL suppressed phosphorylation of Janus Kinase 3 (JAK3) without affecting JAK1. Taken together, OODBL abolished IL-4-induced eotaxin-1 and ALOX15 mRNA expressions by repressing the activation of STAT6 and JAK3. These results suggest that OODBL has a potential therapeutic efficacy on inflammatory diseases especially allergic airway disease as a lead compound.

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References

  1. Holgate, S.T. 2002. Airway inflammation and remodeling in asthma: Current concepts. Molecular Biotechnology 22 (2): 179–189.

    Article  CAS  PubMed  Google Scholar 

  2. Maddox, L., and D.A. Schwartz. 2002. The pathophysiology of asthma. Annual Review of Medicine 53: 477–498.

    Article  CAS  PubMed  Google Scholar 

  3. Colavita, A. M., A. J. Reinach, and S. P. Peters. 2000. Contributing factors to the pathobiology of asthma. The Th1/Th2 paradigm. Clinics in Chest Medicine 21 (2):263–277, viii.

  4. Garcia-Zepeda, E.A., M.E. Rothenberg, R.T. Ownbey, J. Celestin, P. Leder, and A.D. Luster. 1996. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nature Medicine 2 (4): 449–456.

    Article  CAS  PubMed  Google Scholar 

  5. Pease, J.E., and T.J. Williams. 2001. Eotaxin and asthma. Current Opinion in Pharmacology 1 (3): 248–253.

    Article  CAS  PubMed  Google Scholar 

  6. Niimi, A. 2013. Cough, asthma, and cysteinyl-leukotrienes. Pulmonary Pharmacology & Therapeutics 26 (5): 514–519.

    Article  CAS  Google Scholar 

  7. O’Bryan, L., P. Pinkston, V. Kumaraswami, V. Vijayan, G. Yenokida, H.F. Rosenberg, R. Crystal, E.A. Ottesen, and T.B. Nutman. 2003. Localized eosinophil degranulation mediates disease in tropical pulmonary eosinophilia. Infection and Immunity 71 (3): 1337–1342.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Siracusa, M. C., B. S. Kim, J. M. Spergel, and D. Artis. 2013. Basophils and allergic inflammation. The Journal of Allergy and Clinical Immunology 132 (4):789–801; quiz 788.

  9. Matsukura, S., C. Stellato, J.R. Plitt, C. Bickel, K. Miura, S.N. Georas, V. Casolaro, and R.P. Schleimer. 1999. Activation of eotaxin gene transcription by NF-kappa B and STAT6 in human airway epithelial cells. Journal of Immunology 163 (12): 6876–6883.

    CAS  Google Scholar 

  10. Hoeck, J., and M. Woisetschlager. 2001. STAT6 mediates eotaxin-1 expression in IL-4 or TNF-alpha-induced fibroblasts. Journal of Immunology 166 (7): 4507–4515.

    Article  CAS  Google Scholar 

  11. Kuperman, D.A., and R.P. Schleimer. 2008. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Current Molecular Medicine 8 (5): 384–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kuhn, H., and V.B. O'Donnell. 2006. Inflammation and immune regulation by 12/15-lipoxygenases. Progress in Lipid Research 45 (4): 334–356.

    Article  PubMed  Google Scholar 

  13. Chu, H.W., S. Balzar, J.Y. Westcott, J.B. Trudeau, Y. Sun, D.J. Conrad, and S.E. Wenzel. 2002. Expression and activation of 15-lipoxygenase pathway in severe asthma: Relationship to eosinophilic phenotype and collagen deposition. Clinical and Experimental Allergy 32 (11): 1558–1565.

    Article  CAS  PubMed  Google Scholar 

  14. Liu, C., D. Xu, L. Liu, F. Schain, A. Brunnstrom, M. Bjorkholm, H.E. Claesson, and J. Sjoberg. 2009. 15-Lipoxygenase-1 induces expression and release of chemokines in cultured human lung epithelial cells. American Journal of Physiology. Lung Cellular and Molecular Physiology 297 (1): L196–L203.

    Article  CAS  PubMed  Google Scholar 

  15. Zhao, J., B. Maskrey, S. Balzar, K. Chibana, A. Mustovich, H. Hu, J.B. Trudeau, V. O'Donnell, and S.E. Wenzel. 2009. Interleukin-13-induced MUC5AC is regulated by 15-lipoxygenase 1 pathway in human bronchial epithelial cells. American Journal of Respiratory and Critical Care Medicine 179 (9): 782–790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Andersson, C.K., H.E. Claesson, K. Rydell-Tormanen, S. Swedmark, A. Hallgren, and J.S. Erjefalt. 2008. Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling. American Journal of Respiratory Cell and Molecular Biology 39 (6): 648–656.

    Article  CAS  PubMed  Google Scholar 

  17. Heydeck, D., L. Thomas, K. Schnurr, F. Trebus, W.E. Thierfelder, J.N. Ihle, and H. Kuhn. 1998. Interleukin-4 and -13 induce upregulation of the murine macrophage 12/15-lipoxygenase activity: Evidence for the involvement of transcription factor STAT6. Blood 92 (7): 2503–2510.

    CAS  PubMed  Google Scholar 

  18. Conrad, D.J., and M. Lu. 2000. Regulation of human 12/15-lipoxygenase by Stat 6-dependent transcription. American Journal of Respiratory Cell and Molecular Biology 22 (2): 226–234.

    Article  CAS  PubMed  Google Scholar 

  19. Hoshino, A., T. Tsuji, J. Matsuzaki, T. Jinushi, S. Ashino, T. Teramura, K. Chamoto, et al. 2004. STAT6-mediated signaling in Th2-dependent allergic asthma: Critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation. International Immunology 16 (10): 1497–1505.

    Article  CAS  PubMed  Google Scholar 

  20. Vale, K. 2016. Targeting the JAK-STAT pathway in the treatment of ‘Th2-high’ severe asthma. Future Medicinal Chemistry 8 (4): 405–419.

    Article  CAS  PubMed  Google Scholar 

  21. Murata, T., N.I. Obiri, and R.K. Puri. 1998. Structure of and signal transduction through interleukin-4 and interleukin-13 receptors (review). International Journal of Molecular Medicine 1 (3): 551–557.

    CAS  PubMed  Google Scholar 

  22. Kelly-Welch, A.E., E.M. Hanson, M.R. Boothby, and A.D. Keegan. 2003. Interleukin-4 and interleukin-13 signaling connections maps. Science 300 (5625): 1527–1528.

    Article  CAS  PubMed  Google Scholar 

  23. Goenka, S., and M.H. Kaplan. 2011. Transcriptional regulation by STAT6. Immunologic Research 50 (1): 87–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Whan Han, J., B. Gon Lee, Y. Kee Kim, J. Woo Yoon, H. Kyoung Jin, S. Hong, H. Young Lee, K. Ro Lee, and H. Woo Lee. 2001. Ergolide, sesquiterpene lactone from Inula britannica, inhibits inducible nitric oxide synthase and cyclo-oxygenase-2 expression in RAW 264.7 macrophages through the inactivation of NF-kappa B. British Journal of Pharmacology 133 (4): 503–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Khan, A.L., J. Hussain, M. Hamayun, S.A. Gilani, S. Ahmad, G. Rehman, Y.H. Kim, S.M. Kang, and I.J. Lee. 2010. Secondary metabolites from Inula britannica L. and their biological activities. Molecules 15 (3): 1562–1577.

    Article  CAS  PubMed  Google Scholar 

  26. Tang, S.A., H. Zhu, N. Qin, J.Y. Zhou, E. Lee, D.X. Kong, M.H. Jin, and H.Q. Duan. 2014. Anti-inflammatory terpenes from flowers of Inula japonica. Planta Medica 80 (7): 583–589.

    Article  PubMed  Google Scholar 

  27. Pan, M.H., Y.S. Chiou, A.C. Cheng, N. Bai, C.Y. Lo, D. Tan, and C.T. Ho. 2007. Involvement of MAPK, Bcl-2 family, cytochrome c, and caspases in induction of apoptosis by 1, 6-O,O-diacetylbritannilactone in human leukemia cells. Molecular Nutrition & Food Research 51 (2): 229–238.

    Article  CAS  Google Scholar 

  28. Liu, Y.P., J.K. Wen, Y.B. Wu, J. Zhang, B. Zheng, D.Q. Zhang, and M. Han. 2009. 1, 6-O,O-diacetylbritannilactones inhibits Ikappa B kinase beta-dependent NF-kappa B activation. Phytomedicine 16 (2–3): 156–160.

    Article  PubMed  Google Scholar 

  29. Rafi, M.M., N.S. Bai, Ho Chi Tang, R.T. Rosen, E. White, D. Perez, and R.S. Dipaola. 2005. A sesquiterpenelactone from Inula britannica induces anti-tumor effects dependent on Bcl-2 phosphorylation. Anticancer Research 25 (1a): 313–318.

    CAS  PubMed  Google Scholar 

  30. Chen, X., S.A. Tang, E. Lee, Y. Qiu, R. Wang, H.Q. Duan, S. Dan, M. Jin, and D. Kong. 2015. IVSE, isolated from Inula japonica, suppresses LPS-induced NO production via NF-kappa B and MAPK inactivation in RAW264.7 cells. Life Sciences 124: 8–15.

    Article  CAS  PubMed  Google Scholar 

  31. Garcia, G., V. Godot, and M. Humbert. 2005. New chemokine targets for asthma therapy. Current Allergy and Asthma Reports 5 (2): 155–160.

    Article  CAS  PubMed  Google Scholar 

  32. Kuhn, H., S. Banthiya, and K. van Leyen. 2015. Mammalian lipoxygenases and their biological relevance. Biochimica et Biophysica Acta 1851 (4): 308–330.

    Article  CAS  PubMed  Google Scholar 

  33. Lundstrom, S.L., J. Yang, H.J. Kallberg, S. Thunberg, G. Gafvelin, J.Z. Haeggstrom, R. Gronneberg, et al. 2012. Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation. PloS One 7 (3): e33780.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ono, E., H. Mita, M. Taniguchi, N. Higashi, M. Hasegawa, E. Miyazaki, T. Kumamoto, and K. Akiyama. 2009. Concentration of 14, 15-leukotriene C4 (eoxin C4) in bronchoalveolar lavage fluid. Clinical and Experimental Allergy 39 (9): 1348–1352.

    Article  CAS  PubMed  Google Scholar 

  35. Han, H., D. Xu, C. Liu, H.E. Claesson, M. Bjorkholm, and J. Sjoberg. 2014. Interleukin-4-mediated 15-lipoxygenase-1 trans-activation requires UTX recruitment and H3K27me3 demethylation at the promoter in A549 cells. PloS One 9 (1): e85085.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chen, X.H., B.K. Patel, L.M. Wang, M. Frankel, N. Ellmore, R.A. Flavell, W.J. LaRochelle, and J.H. Pierce. 1997. Jak 1 expression is required for mediating interleukin-4-induced tyrosine phosphorylation of insulin receptor substrate and Stat 6 signaling molecules. The Journal of Biological Chemistry 272 (10): 6556–6560.

    Article  CAS  PubMed  Google Scholar 

  37. Oakes, S.A., F. Candotti, J.A. Johnston, Y.Q. Chen, J.J. Ryan, N. Taylor, X. Liu, et al. 1996. Signaling via IL-2 and IL-4 in JAK3-deficient severe combined immunodeficiency lymphocytes: JAK3-dependent and independent pathways. Immunity 5 (6): 605–615.

    Article  CAS  PubMed  Google Scholar 

  38. Mikita, T., D. Campbell, P. Wu, K. Williamson, and U. Schindler. 1996. Requirements for interleukin-4-induced gene expression and functional characterization of Stat 6. Molecular and Cellular Biology 16 (10): 5811–5820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fruman, D.A., and G. Bismuth. 2009. Fine tuning the immune response with PI3K. Immunological Reviews 228 (1): 253–272.

    Article  CAS  PubMed  Google Scholar 

  40. Duan, W., A.M. Aguinaldo Datiles, B.P. Leung, C.J. Vlahos, and W.S. Wong. 2005. An anti-inflammatory role for a phosphoinositide 3-kinase inhibitor LY294002 in a mouse asthma model. International Immunopharmacology 5 (3): 495–502.

    Article  CAS  PubMed  Google Scholar 

  41. Lee, K.S., H.K. Lee, J.S. Hayflick, Y.C. Lee, and K.D. Puri. 2006. Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. The FASEB Journal 20 (3): 455–465.

    Article  CAS  PubMed  Google Scholar 

  42. Doukas, J., L. Eide, K. Stebbins, A. Racanelli-Layton, L. Dellamary, M. Martin, E. Dneprovskaia, et al. 2009. Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100-115 [3-[2, 4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. The Journal of Pharmacology and Experimental Therapeutics 328 (3): 758–765.

    Article  CAS  PubMed  Google Scholar 

  43. Hosokawa, Y., I. Hosokawa, S. Shindo, K. Ozaki, and T. Matsuo. 2016. IL-4 modulates CCL11 and CCL20 productions from IL-1beta-stimulated human periodontal ligament cells. Cellular Physiology and Biochemistry 38 (1): 153–159.

    Article  CAS  PubMed  Google Scholar 

  44. Wu, D., J. Zhou, H. Bi, L. Li, W. Gao, M. Huang, I.M. Adcock, P.J. Barnes, and X. Yao. 2014. CCL11 as a potential diagnostic marker for asthma? The Journal of Asthma 51 (8): 847–854.

    Article  CAS  PubMed  Google Scholar 

  45. Hogan, S.P. 2007. Recent advances in eosinophil biology. International Archives of Allergy and Immunology 143 (Suppl 1): 3–14.

    Article  PubMed  Google Scholar 

  46. Nakajima, H., and K. Takatsu. 2007. Role of cytokines in allergic airway inflammation. International Archives of Allergy and Immunology 142 (4): 265–273.

    Article  CAS  PubMed  Google Scholar 

  47. Jayawickreme, S.P., T. Gray, P. Nettesheim, and T. Eling. 1999. Regulation of 15-lipoxygenase expression and mucus secretion by IL-4 in human bronchial epithelial cells. The American Journal of Physiology 276 (4 Pt 1): L596–L603.

    CAS  PubMed  Google Scholar 

  48. Shankaranarayanan, P., P. Chaitidis, H. Kuhn, and S. Nigam. 2001. Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. The Journal of Biological Chemistry 276 (46): 42753–42760.

    Article  CAS  PubMed  Google Scholar 

  49. Chung, H.S., Y. Kim, S.J. Oh, H. Kim, S.I. Choi, Y. Zhang, J.H. Jeong, and H. Bae. 2013. A synthetic compound, 4-acetyl-3-methyl-6-(3,4,5-trimethoxyphenyl)pyrano[3,4-c]pyran-1,8-dione, ameliorates ovalbumin-induced asthma. Bioorganic & Medicinal Chemistry 21 (21): 6359–6365.

    Article  CAS  Google Scholar 

  50. Hebenstreit, D., G. Wirnsberger, J. Horejs-Hoeck, and A. Duschl. 2006. Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine & Growth Factor Reviews 17 (3): 173–188.

    Article  CAS  Google Scholar 

  51. Oh, C.K., G.P. Geba, and N. Molfino. 2010. Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma. European Respiratory Review 19 (115): 46–54.

    Article  CAS  PubMed  Google Scholar 

  52. Cheng, C., W.E. Ho, F.Y. Goh, S.P. Guan, L.R. Kong, W.Q. Lai, B.P. Leung, and W.S. Wong. 2011. Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. PloS One 6 (6): e20932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China

    Xi Chen, Ning Ji, Sheng-an Tang, Ran Wang, Yuling Qiu, Hongquan Duan, Dexin Kong & Meihua Jin

  2. Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin, 300020, China

    Xi Chen

  3. Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

    Nan Qin, Hongquan Duan & Dexin Kong

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  1. Xi Chen
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  2. Ning Ji
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Correspondence to Meihua Jin.

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Funding Sources

This study was supported by a grant from the National Natural Science Foundation of China (81202542, 81402802, 81373441); the Natural Science Foundation of Tianjin (13JCYBJC24800, 15JCQNJC13700); the New Teacher’s Fund for Doctor Stations from Ministry of Education, China (20121202120009); and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.

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Chen, X., Ji, N., Qin, N. et al. 1,6-O,O-Diacetylbritannilactone Inhibits Eotaxin-1 and ALOX15 Expression Through Inactivation of STAT6 in A549 Cells. Inflammation 40, 1967–1974 (2017). https://doi.org/10.1007/s10753-017-0637-y

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