Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Apigenin Inhibits Tumor Necrosis Factor-α-Induced Production and Gene Expression of Mucin through Regulating Nuclear Factor-Kappa B Signaling Pathway in Airway Epithelial Cells

  • Seo, Hyo-Seok (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Sikder, Mohamed Asaduzzaman (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Lee, Hyun Jae (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Ryu, Jiho (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Lee, Choong Jae (Department of Pharmacology, School of Medicine, Chungnam National University)
  • Received : 2014.08.14
  • Accepted : 2014.09.01
  • Published : 2014.11.30
Download PDF
⟨ Previous Next ⟩

Abstract

In the present study, we investigated whether apigenin significantly affects tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$)-induced production and gene expression of MUC5AC mucin in airway epithelial cells. Confluent NCI-H292 cells were pretreated with apigenin for 30 min and then stimulated with TNF-${\alpha}$ for 24 h or the indicated periods. The MUC5AC mucin gene expression and mucin protein production were measured by reverse transcription - polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Apigenin significantly inhibited MUC5AC mucin production and down-regulated MUC5AC gene expression induced by TNF-${\alpha}$ in NCI-H292 cells. To elucidate the action mechanism of apigenin, effect of apigenin on TNF-${\alpha}$-induced nuclear factor kappa B (NF-${\kappa}B$) signaling pathway was also investigated by western blot analysis. Apigenin inhibited NF-${\kappa}B$ activation induced by TNF-${\alpha}$. Inhibition of inhibitory kappa B kinase (IKK) by apigenin led to the suppression of inhibitory kappa B alpha ($I{\kappa}B{\alpha}$) phosphorylation and degradation, p65 nuclear translocation. This, in turn, led to the down-regulation of MUC5AC protein production in NCI-H292 cells. Apigenin also has an influence on upstream signaling of IKK because it inhibited the expression of adaptor protein, receptor interacting protein 1 (RIP1). These results suggest that apigenin can regulate the production and gene expression of mucin through regulating NF-${\kappa}B$ signaling pathway in airway epithelial cells.

Keywords

References

  1. Chinnaiyan, A. M., O'Rourke, K., Tewari, M. and Dixit, V. M. (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81, 505-512. https://doi.org/10.1016/0092-8674(95)90071-3
  2. Clere, N., Faure, S., Martinez, M.C. and Andriantsitohaina, R. (2011) Anticancer properties of flavonoids: roles in various stages of carcinogenesis. Cardiovasc. Hematol. Agents Med. Chem. 9, 62-77. https://doi.org/10.2174/187152511796196498
  3. Cohn, L., Whittaker, L., Niu, N., and Homer, R.J. (2002) Cytokine regulation of mucus production in a model of allergic asthma. Novartis Found. Symp. 248, 201-213.
  4. Fischer, B. M., Rochelle, L. G., Voynow, J. A., Akley, N. J. and Adler, K. B. (1999) Tumor necrosis factor-alpha stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cells in vitro. Am. J. Respir. Cell Mol. Biol. 20, 413-422. https://doi.org/10.1165/ajrcmb.20.3.3393
  5. Heo, H. J., Lee, H. J., Kim,Y. S., Kang, S. S., Son, K. H., Seok, J. H., Seo, U. K. and Lee, C. J. (2007) Effects of baicalin and wogonin on mucin release from cultured airway epithelial cells. Phytother. Res. 21, 1130-1134. https://doi.org/10.1002/ptr.2222
  6. Heo, H. J., Lee, S. Y., Lee, M. N., Lee, H. J., Seok, J. H. and Lee, C. J. (2009) Genistein and curcumin suppress epidermal growth factor-induced MUC5AC mucin production and gene expression from human airway epithelial cells. Phytother. Res. 23, 1458-1461. https://doi.org/10.1002/ptr.2801
  7. Hsu, H., Huang, J., Shu, H. B., Baichwal, V. and Goeddel, D. V. (1996) TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4, 387-396. https://doi.org/10.1016/S1074-7613(00)80252-6
  8. Hsu, H., Xiong, J. and Goeddel, D. V. (1995) The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 81, 495-504. https://doi.org/10.1016/0092-8674(95)90070-5
  9. Illek, B. and Fischer, H. (1998) Flavonoids stimulate Cl conductance of human airway epithelium in vitro and in vivo. Am. J. Physiol. 275, L902-L910.
  10. Kim, J. O., Sikder, M. A., Lee, H. J., Rahman, M., Kim, J. H., Chang, G. T. and Lee, C. J. (2012) Phorbol ester or epidermal growth factor-induced MUC5AC mucin gene expression and production from airway epithelial cells are inhibited by apigenin and wogonin. Phytother. Res. 26, 1784-1788. https://doi.org/10.1002/ptr.4650
  11. Lee, H. J., Lee, S. Y., Lee, M. N., Kim, J. H., Chang, G. T., Seok, J. H. and Lee, C. J. (2011) Inhibition of secretion, production and gene expression of mucin from cultured airway epithelial cells by prunetin. Phytother. Res. 25, 1196-1200. https://doi.org/10.1002/ptr.3362
  12. Li, J. D., Dohrman, A. F., Gallup, M., Miyata, S., Gum, J. R., Kim, Y. S., Nadel, J. A., Prince, A. and Basbaum, C. B. (1997) Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc. Natl. Acad. Sci. USA. 94, 967-972. https://doi.org/10.1073/pnas.94.3.967
  13. Li, Q. And Verma, I. M. (2002) NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2, 725-734. https://doi.org/10.1038/nri910
  14. McVean, M., Weinberg, W. C. and Pelling, J. C. (2002) A p21(waf1)-independent pathway for inhibitory phosphorylation of cyclin-dependent kinase p34(cdc2) and concomitant G(2)/M arrest by the chemopreventive flavonoid apigenin. Mol. Carcinog. 33, 36-43. https://doi.org/10.1002/mc.10016
  15. Paoletti, T., Fallarini, S., Gugliesi, F., Minassi, A., Appendino, G and Lombardi, G. (2009) Anti-inflammatory and vascularprotective properties of 8-prenylapigenin. Eur. J. Pharmacol. 620, 120-130. https://doi.org/10.1016/j.ejphar.2009.08.015
  16. Romano, B., Pagano, E., Montanaro, V., Fortunato, A. L., Milic, N. and Borrelli, F. (2013) Novel insights into the pharmacology of flavonoids. Phytother. Res. 27, 1588-1596. https://doi.org/10.1002/ptr.5023
  17. Shao, M. X., Ueki, I. F. and Nadel, J. A. (2003) Tumor necrosis factor alpha-converting enzyme mediated MUC5AC mucin expression in cultured human airway epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 100, 11618-11623. https://doi.org/10.1073/pnas.1534804100
  18. Sikder, M. A., Lee, H. J., Mia, M. Z., Park, S. H., Ryu, J., Kim, J. H., Min, S. Y., Hong, J. H., Seok, J. H. and Lee, C. J. (2014) Inhibition of TNF-${\alpha}$-induced MUC5AC mucin gene expression and production by wogonin through the inactivation of NF-${\kappa}B$ signaling in airway epithelial cells. Phytother. Res. 28, 62-68. https://doi.org/10.1002/ptr.4954
  19. Song, K., Lee, W. J., Chung, K. C., Koo, J. S., Yang, E. J., Choi, J. Y. and Yoon, J. H. (2003) Interleukin-1 beta and tumor necrosis factor-alpha induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen activated protein kinases-MSK1-CREB activation in human airway epithelial cells. J. Biol. Chem. 278, 23243-23250. https://doi.org/10.1074/jbc.M300096200
  20. Sprenger, L., Goldmann, T., Vollmer, E., Steffen, A., Wollenberg, B., Zabel, P. and Hauber, H. P. (2011) Dexamethasone and N-acetylcysteine attenuate Pseudomonas aeruginosa-induced mucus expression in human airways. Pulm. Pharmacol. Ther. 24, 232-239. https://doi.org/10.1016/j.pupt.2010.11.003
  21. Stanger, B. Z., Leder, P., Lee, T. H., Kim, E. and Seed, B. (1995) RIP: a novel protein containing a death domain that interacts with Fas/ APO-1 (CD95) in yeast and causes cell death. Cell 81, 513-523. https://doi.org/10.1016/0092-8674(95)90072-1
  22. Takeyama, K., Dabbagh, K., Jeong, Shim J., Dao-Pick, T., Ueki, I. F. and Nadel, J. A. (2000) Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils. J. Immunol. 164, 1546-1552. https://doi.org/10.4049/jimmunol.164.3.1546
  23. Takeyama, K., Dabbagh, K., Lee, H., Agusti, C., Lausier, J. A., Ueki, I. F., Grattan, K. M. and Nadel, J. A. (1999) Epidermal growth factor system regulates mucin production in airways. Proc. Natl. Acad. Sci. U.S.A. 96, 3081-3086. https://doi.org/10.1073/pnas.96.6.3081
  24. Voynow, J. A. and Rubin, B. K. (2009) Mucins, mucus, and sputum. Chest 135, 505-512. https://doi.org/10.1378/chest.08-0412
  25. Wu, D. G., Yu, P., Li, J. W., Jiang, P., Sun, J., Wang, H. Z., Zhang, L. D., Wen, M. B. and Bie, P. (2014) Apigenin potentiates the growth inhibitory effects by IKK-${\beta}$-mediated NF-${\kappa}B$ activation in pancreatic cancer cells. Toxicol. Lett. 224, 157-164. https://doi.org/10.1016/j.toxlet.2013.10.007
  26. Yin, F., Giuliano, A. E., Law, R. E. and Van Herle, A. J. (2001) Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells. Anticancer Res. 21, 413-420.
  27. Zhong, Y., Krisanapun, C., Lee, S. H., Nualsanit, T., Sams, C., Peungvicha, P and Baek, S. J. (2010) Molecular targets of apigenin in colorectal cancer cells: involvement of p21, NAG-1 and p53. Eur. J. Cancer 46, 3365-3374. https://doi.org/10.1016/j.ejca.2010.07.007
  28. Zhou, Y., Rajabi, H. and Kufe, D. (2011) Mucin 1 C-terminal subunit oncoprotein is a target for small-molecule inhibitors. Mol. Pharmacol. 79, 886-893. https://doi.org/10.1124/mol.110.070797

Cited by

  1. 1-(2,3-Dibenzimidazol-2-ylpropyl)-2-methoxybenzene Is a Syk Inhibitor with Anti-Inflammatory Properties vol.21, pp.4, 2016, https://doi.org/10.3390/molecules21040508
  2. In vivo TNF- and IL-1 inhibitory activity of phenolics isolated from Trachelospermum jasminoides (Lindl.) Lem vol.9, pp.2, 2015, https://doi.org/10.5897/JMPR2014.5705
  3. Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway vol.37, pp.7, 2016, https://doi.org/10.1007/s13277-016-4864-x
  4. Plant flavones enhance antimicrobial activity of respiratory epithelial cell secretions against Pseudomonas aeruginosa vol.12, pp.9, 2017, https://doi.org/10.1371/journal.pone.0185203
  5. Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor vol.292, pp.20, 2017, https://doi.org/10.1074/jbc.M116.771949
  6. Effects of Nodakenin, Columbianadin, and Umbelliferone Isolated from the Roots of Angelica decursiva on the Gene Expression and Production of MUC5AC Mucin from Human Airway Epithelial NCI-H292 Cells vol.23, pp.3, 2014, https://doi.org/10.20307/nps.2017.23.3.201
  7. Diclofenac Inhibits Phorbol Ester-Induced Gene Expression and Production of MUC5AC Mucin via Affecting Degradation of IkBα and Translocation of NF-kB p65 in NCI-H292 Cells vol.28, pp.5, 2014, https://doi.org/10.4062/biomolther.2020.090
  8. Kaempferol Regulates the Expression of Airway MUC5AC Mucin Gene via IκBα-NF-κB p65 and p38-p44/42-Sp1 Signaling Pathways vol.29, pp.3, 2014, https://doi.org/10.4062/biomolther.2020.149
  9. Apigenin Modulates Dendritic Cell Activities and Curbs Inflammation Via RelB Inhibition in the Context of Neuroinflammatory Diseases vol.16, pp.2, 2014, https://doi.org/10.1007/s11481-020-09933-8
  10. Eriodictyol Inhibits the Production and Gene Expression of MUC5AC Mucin via the IκBα-NF-κB p65 Signaling Pathway in Airway Epithelial Cells vol.29, pp.6, 2021, https://doi.org/10.4062/biomolther.2021.091
  11. Apigenin role as cell-signaling pathways modulator: implications in cancer prevention and treatment vol.21, pp.1, 2014, https://doi.org/10.1186/s12935-021-01888-x