Biomolecules & Therapeutics

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

DOI QR Code

Kaempferol Regulates the Expression of Airway MUC5AC Mucin Gene via IκBα-NF-κB p65 and p38-p44/42-Sp1 Signaling Pathways

  • Li, Xin (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Jin, Fengri (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Lee, Hyun Jae (Smith Liberal Arts College and Department of Addiction Science, Graduate School, Sahmyook University) ;
  • Lee, Choong Jae (Department of Pharmacology, School of Medicine, Chungnam National University)
  • Received : 2020.08.25
  • Accepted : 2020.11.12
  • Published : 2021.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

In the present study, kaempferol, a flavonoidal natural compound found in Polygonati Rhizoma, was investigated for its potential effect on the gene expression and production of airway MUC5AC mucin. A human respiratory epithelial NCI-H292 cells was pretreated with kaempferol for 30 min and stimulated with epidermal growth factor (EGF) or phorbol 12-myristate 13-acetate (PMA), for the following 24 h. The effect on PMA-induced nuclear factor kappa B (NF-κB) signaling pathway or EGF-induced mitogen-activated protein kinase (MAPK) signaling pathway was investigated. Kaempferol suppressed the production and gene expression of MUC5AC mucins, induced by PMA through the inhibition of degradation of inhibitory kappa Bα (IκBα), and NF-κB p65 nuclear translocation. Also, kaempferol inhibited EGF-induced gene expression and production of MUC5AC mucin through regulating the phosphorylation of EGFR, phosphorylation of p38 MAPK and extracellular signal-regulated kinase (ERK) 1/2 (p44/42), and the nuclear expression of specificity protein-1 (Sp1). These results suggest kaempferol regulates the gene expression and production of mucin through regulation of NF-κB and MAPK signaling pathways, in human airway epithelial cells.

Keywords

References

  1. Briggs, M. R., Kadonaga, J. T., Bell, S. P. and Tjian, R. (1986) Purification and biochemical characterization of the promoter-specific transcription factor, Sp1. Science 234, 47-52. https://doi.org/10.1126/science.3529394
  2. Burgel, P. R., Lazarus, S. C., Tam, D. C., Ueki, I. F., Atabai, K., Birch, M. and Nadel, J. A. (2001) Human eosinophils induce mucin production in airway epithelial cells via epidermal growth factor receptor activation. J. Immunol. 167, 5948-5954. https://doi.org/10.4049/jimmunol.167.10.5948
  3. Choi, B. S., Kim, Y. J., Choi, J. S., Lee, H. J. and Lee, C. J. (2019) Obtusifolin isolated from the seeds of Cassia obtusifolia regulates the gene expression and production of MUC5AC mucin in airway epithelial cells via affecting NF-κB pathway. Phytother. Res. 33, 919-928. https://doi.org/10.1002/ptr.6284
  4. Choi, B. S., Kim, Y. J., Yoon, Y. P., Lee, H. J. and Lee, C. J. (2018) Tussilagone suppressed the production and gene expression of MUC5AC mucin via regulating nuclear factor-kappa B signaling pathway in airway epithelial cells. Korean J. Physiol. Pharmacol. 22, 671-677. https://doi.org/10.4196/kjpp.2018.22.6.671
  5. Devi, K. P., Malar, D. S., Nabavi, S. F., Sureda, A., Xiao, J., Nabavi, S. M. and Daglia, M. (2015) Kaempferol and inflammation: From chemistry to medicine. Pharmacol. Res. 99, 1-10. https://doi.org/10.1016/j.phrs.2015.05.002
  6. Fujisawa, T., Velichko, S., Thai, P., Hung, L. Y., Huang, F. and Wu, R. (2009) Regulation of airway MUC5AC expression by IL-1beta and IL-17A; the NF-kappa B paradigm. J. Immunol. 183, 6236-6243. https://doi.org/10.4049/jimmunol.0900614
  7. Garvin, L. M., Chen, Y., Damsker, J. M. and Rose, M. C. (2016) A novel dissociative steroid VBP15 reduces MUC5AC gene expression in airway epithelial cells but lacks the GRE mediated transcriptional properties of dexamethasone. Pulm. Pharmacol. Ther. 38, 17-26. https://doi.org/10.1016/j.pupt.2016.04.004
  8. 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
  9. 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
  10. Hewson, C. A., Edbrooke, M. R. and Johnston, S. L. (2004) PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells via PKC, EGF/TGF-alpha, Ras/Raf, MEK, REK and Sp1-dependent mechanisms. J. Mol. Biol. 344, 683-695. https://doi.org/10.1016/j.jmb.2004.09.059
  11. Ishinaga, H., Takeuchi, K., Kishioka, C., Suzuki, S., Basbaum, C. and Majima, Y. (2005) Pranlukast inhibits NF-kappaB activation and MUC2 gene expression in cultured human epithelial cells. Pharmacology 73, 89-96. https://doi.org/10.1159/000081294
  12. Kadonaga, J. T., Carner, K. R., Masiarz, F. R. and Tjian, R. (1987) Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell 51, 1079-1090. https://doi.org/10.1016/0092-8674(87)90594-0
  13. Kim, E. J., Yoon, Y. P., Woo, K. W., Kim, J. H., Min, S. Y., Lee, H. J., Lee, S. K., Hong, J. H., Lee, K. R. and Lee, C. J. (2016) Verticine, ebeiedine and suchengbeisine isolated from the bulbs of Fritillaria thunbergii Miq. inhibited the gene expression and production of MUC5AC mucin from human airway epithelial cells. Phytomedicine 23, 95-104. https://doi.org/10.1016/j.phymed.2015.12.016
  14. 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
  15. Kurakula, K., Hamers, A. A., van Loenen, P. and de Vries, C. J. (2015) 6-Mercaptopurine reduces cytokine and Muc5ac expression involving inhibition of NFκB activation in airway epithelial cells. Respir. Res. 16, 73. https://doi.org/10.1186/s12931-015-0236-0
  16. Kwon, S. H., Nam, J. I., Kim, S. H., Kim, J. H., Yoon, J. H. and Kim, K. S. (2009) Kaempferol and quercetin, essential ingredients in Ginkgo biloba extract, inhibit interleukin-1beta-induced MUC5AC gene expression in human airway epithelial cells. Phytother. Res. 23, 1708-1712. https://doi.org/10.1002/ptr.2817
  17. Laos, S., Baeckstrom, D. and Hansson, G. C. (2006) Inhibition of NF-kappaB activation and chemokine expression by the leukocyte glycoprotein, CD43, in colon cancer cells. Int. J. Oncol. 28, 695-704.
  18. Lee, H. J., Lee, S. Y., Bae, H. S., Kim, J. H., Chang, G. T., Seok, J. H. and Lee, C. J. (2011) Inhibition of airway MUC5AC mucin production and gene expression induced by epidermal growth factor or phorbol ester by glycyrrhizin and carbenoxolone. Phytomedicine 18, 743-747. https://doi.org/10.1016/j.phymed.2010.11.003
  19. Lee, H. J., Park, J. S., Yoon, Y. P., Shin, Y. J., Lee, S. K., Kim, Y. S., Hong, J. H., Son, K. H. and Lee, C. J. (2015) Dioscin and methylprotodioscin isolated from the root of Asparagus cochinchinensis suppressed the gene expression and production of airway MUC5AC mucin induced by phorbol ester and growth factor. Phytomedicine 22, 568-572. https://doi.org/10.1016/j.phymed.2015.03.009
  20. Lemmon, M. A. and Schlessinger, J. (1994) Regulation of signal transduction and signal diversity by receptor oligomerization. Trends Biochem. Sci. 19, 459-463. https://doi.org/10.1016/0968-0004(94)90130-9
  21. 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. U.S.A. 94, 967-972. https://doi.org/10.1073/pnas.94.3.967
  22. Li, X., Jin, F., Lee, H. J. and Lee, C. J. (2020) Recent advances in the development of novel drug candidates for regulating the secretion of pulmonary mucus. Biomol. Ther. (Seoul) 28, 293-301. https://doi.org/10.4062/biomolther.2020.002
  23. Mata, M., Sarria, B., Buenestado, A., Cortijo, J., Cerda, M. and Morcillo, E. J. (2005) Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax 60, 144-152. https://doi.org/10.1136/thx.2004.025692
  24. Park, M. Y., Ji, G. E. and Sung, M. K. (2012a) Dietary kaempferol suppresses inflammation of dextran sulfate sodium-induced colitis in mice. Dig. Dis. Sci. 57, 355-363. https://doi.org/10.1007/s10620-011-1883-8
  25. Park, S. H., Gong, J. H., Choi, Y. J., Kang, M. K., Kim, Y. H. and Kang, Y. H. (2015) Kaempferol inhibits endoplasmic reticulum stress-associated mucus hypersecretion in airway epithelial cells and ovalbumin-sensitized mice. PLoS ONE 10, e0143526. https://doi.org/10.1371/journal.pone.0143526
  26. Park, U. H., Jeong, J. C., Jang, J. S., Sung, M. R., Youn, H., Lee, S. J., Kim, E. J. and Um, S. J. (2012b) Negative regulation of adipogenesis by kaempferol, a component of Rhizoma Polygonati falcatum in 3T3-L1 cells. Biol. Pharm. Bull. 35, 1525-1533. https://doi.org/10.1248/bpb.b12-00254
  27. Podder, B., Song, K. S., Song, H. Y. and Kim, Y. S. (2014) Cytoprotective effect of kaempferol on paraquat-exposed BEAS-2B cells via modulating expression of MUC5AC. Biol. Pharm. Bull. 37, 1486-1494. https://doi.org/10.1248/bpb.b14-00239
  28. Rogers, D. F. and Barnes, P. J. (2006) Treatment of airway mucus hypersecretion. Ann. Med. 38, 116-125. https://doi.org/10.1080/07853890600585795
  29. Rogers, D. F. (2007) Mucoactive agents for airway mucus hypersecretory diseases. Respir. Care 52, 1176-1193.
  30. Ryu, J., Lee, H. J., Park, S. H., Kim, J., Lee, D., Lee, S. K., Kim, Y. S., Hong, J. H., Seok, J. H. and Lee, C. J. (2014) Effects of the root of Platycodon grandiflorum on airway mucin hypersecretion in vivo and platycodin D(3) and deapi-platycodin on production and secretion of airway mucin in vitro. Phytomedicine 21, 529-533. https://doi.org/10.1016/j.phymed.2013.10.004
  31. Ryu, J., Lee, H. J., Park, S. H., Sikder, M. A., Kim, J. O., Hong, J. H., Seok, J. H. and Lee, C. J. (2013) Effect of prunetin on TNF-α-induced MUC5AC mucin gene expression, production, degradation of IκB and translocation of NF-κB p65 in human airway epithelial cells. Tuberc. Respir. Dis. (Seoul) 75, 205-209. https://doi.org/10.4046/trd.2013.75.5.205
  32. Seo, H. S., Sikder, M. A., Lee, H. J., Ryu, J. and Lee, C. J. (2014) 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. Biomol. Ther. (Seoul) 22, 525-531. https://doi.org/10.4062/biomolther.2014.094
  33. Shao, M. X., Ueki, I. F. and Nadel, J. A. (2003) TNF-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
  34. 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-α-induced MUC5AC mucin gene expression and production by wogonin through the inactivation of NF-κB signaling in airway epithelial cells. Phytother. Res. 28, 62-68. https://doi.org/10.1002/ptr.4954
  35. Sprenger, L., Goldmann, T., Vollmer, E., Steffen, A., Wollenberg, B., Zabel, P. and Hauber, H. P. (2011) Dexamethasone and N-acetyl-cysteine 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
  36. Takeyama, K., Dabbagh, K., Shim, J. 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
  37. 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
  38. Voynow, J. A. and Rubin, B. K. (2009) Mucins, mucus, and sputum. Chest 135, 505-512. https://doi.org/10.1378/chest.08-0412
  39. Wetzker, R. and Bohmer, F. D. (2003) Transactivation joins multiple tracks to the ERK/MAPK cascade. Nat. Rev. Mol. Cell Biol. 4, 651-657. https://doi.org/10.1038/nrm1173
  40. Wu, D. Y., Wu, R., Reddy, S. P, Lee, Y. C. and Chang, M. M. (2007) Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate. Am. J. Pathol. 170, 20-32. https://doi.org/10.2353/ajpath.2007.060452