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Acetaldehyde-induced interleukin-1β and tumor necrosis factor-α production is inhibited by berberine through nuclear factor-κB signaling pathway in HepG2 cells

Journal of Biomedical Science volume 12, pages 791–801 (2005)Cite this article

Summary

Alcoholic liver disease (ALD) is one of the most common liver diseases in the world. Increased levels of proinflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), have been correlated with the patients affected by ALD. However, the direct effect of alcohol in the induction of IL-1β and TNF-α has not been clarified. In this study, we demonstrated that acetaldehyde, the metabolic product of ethanol, was able to induce IL-1β and TNF-α production in HepG2 cells. Nuclear factor-κB (NF-κB), the transcription factor involved in the regulation of cytokine production, was also activated by acetaldehyde through inhibitory κB-α (IκB-α) phosphorylation and degradation. However, the NF-κB inhibitors, such as aspirin, cyclosporin A and dexamethasone, inhibited both the acetaldehyde-induced NF-κB activity and the induced cytokine production. Therefore, these data suggested that acetaldehyde stimulated IL-1β and TNF-α production via the regulation of NF-κB signaling pathway. By screening 297 controlled Chinese medicinal herbs supervised by Committee on Chinese Medicine and Pharmacy at Taiwan, we found that Coptis chinensis (Huang-Lien) and Phellodendron amurense (Huang-Po) were capable of inhibiting acetaldehyde-induced NF-κB activity. Berberine, the major ingredient of these herbs, abolished acetaldehyde-induced NF-κB activity and cytokine production in a dose-dependent manner. Moreover, its inhibitory ability was through the inhibition of induced IκB-α phosphorylation and degradation. In conclusion, we first linked the acetaldehyde-induced NF-κB activity to the induced proinflammatory cytokine production in HepG2 cells. Our findings also suggested the potential role of berberine in the treatment of ALD.

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References

  1. Lieber C.S., 1993 Alcoholic liver disease: a public health issue in need of a public health approach Semin. Liver Dis 13:105–107

    PubMed  CAS  Google Scholar 

  2. Lieber C.S., 1994. Alcohol and the liver Gastroenterology 106:1085–1105

    PubMed  CAS  Google Scholar 

  3. Tsukamoto H., Lu S.C., 2001. Current concepts in the pathogenesis of alcoholic liver injury FASEB J. 15:1335–1349

    Article  PubMed  CAS  Google Scholar 

  4. Kanimura S., Tsukamoto H., 1995. Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease Hepatology 21:1304–1309

    Article  Google Scholar 

  5. Yin M., Wheeler M.D., Kono H., Bradford B.U., Gallucci R.M., Luster M.I., Thurman R.G., 1999. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice Gastroenterology 117:942–952

    Article  PubMed  CAS  Google Scholar 

  6. Lieber C.S., 1990. Mechanism of ethanol induced hepatic injury Pharmacol. Ther. 46:1–41

    Article  PubMed  CAS  Google Scholar 

  7. Pares A., Potter J.J., Rennie L., Mezey E., 1994. Acetaldehyde activates the promoter of the mouse alpha 2(I) collagen gene Hepatology 19:498–503

    Article  PubMed  CAS  Google Scholar 

  8. Carter E.A., Wands J.R., 1988. Ethanol-induced inhibition of liver cell function: I. Effect of ethanol on hormone stimulated hepatocyte DNA synthesis and the role of ethanol metabolism Alcohol Clin. Exp. Res. 12:555–562

    PubMed  Article  CAS  Google Scholar 

  9. Lands W.E.M., 1995. Cellular signals in alcohol induced liver injury. A review. Alcohol Clin. Exp. Res. 19:928–938

    PubMed  Article  CAS  Google Scholar 

  10. Yamamoto Y., Gaynor R.B., 2001 Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer J. Clin. Invest. 107:135–142

    PubMed  CAS  Google Scholar 

  11. Baldwin A.S., 1996. The NF-κB and IκB proteins: new discoveries and insights Annu. Rev. Immunol. 14:649–683

    Article  PubMed  CAS  Google Scholar 

  12. Barnes P.J., Karin M., 1997. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases N. Engl. J. Med. 336:1066–1071

    Article  PubMed  CAS  Google Scholar 

  13. Baeuerle P.A., Baichwal V.R., 1997. NF-κB as a frequent target for immunosuppressive and anti-inflammatory molecules Adv. Immunol. 65:111–137

    PubMed  CAS  Article  Google Scholar 

  14. Hsiang C.Y., Lai I.L., Chao D.C., Ho T.Y., 2002. Differential regulation of activator protein 1 activity by glycyrrhizin Life Sci. 70:1643–1656

    Article  PubMed  CAS  Google Scholar 

  15. Khoruts A., Stanke L., McClain C.F., Logan G., Allen J.I., 1991. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients Hepatology 13:267–276

    Article  PubMed  CAS  Google Scholar 

  16. Pahl H.L., 1999. Activators and target genes of Rel/NF-κB transcription factors Oncogene 18:6853–6866

    PubMed  Article  CAS  Google Scholar 

  17. Yin M.J., Yamamoto Y., Gaynor R.B., 1998. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β Nature 396:77–80

    Article  PubMed  CAS  Google Scholar 

  18. Marienfeld R., Neumann M., Chuvpilo S., Escher C., Kneitz B., Avots A., Schimpl A., Serfling E., 1997 Cyclosporin A interferes with the inducible degradation of NF-κB inhibitors, but not with the processing of p105/NF-κB1 in T cells Eur. J. Immunol. 27:1601–1609

    PubMed  Article  CAS  Google Scholar 

  19. DeBosscher K., Berghe W.V., Vermeulen L., Plaisance S., Boone E., Haegeman G., 2000. Glucocorticoids repress NF-κB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell Proc. Natl. Acad. Sci. USA 97:3919–3924

    Article  PubMed  CAS  Google Scholar 

  20. McClain C.J., Barve S., Deaciuc I., Kugelmas M., Hill D., 1999. Cytokines in alcoholic liver disease Semin. Liver Dis. 19:205–219

    PubMed  CAS  Google Scholar 

  21. Tilg H., Diehl A.M., 2000. Cytokines in alcoholic and nonalcoholic steatohepatitisN. Engl. J. Med. 343:1467–1476

    Article  PubMed  CAS  Google Scholar 

  22. Rodríguez-Rodríguez E., González-Reimers E., Santolaria-Fernández F., Milena-Abril A., Rodríguez-Moreno F., Oramas-Rodríguez J., Martinez-Riera A., 1995. Cytokine levels in acute alcoholic hepatitis: a sequential study Drug Alcohol Depend 39:23–27

    Article  PubMed  Google Scholar 

  23. Valles S.L., Blanco A.M., Azorin I., Guasch R., Pascual M., Gomez-Lechon M.J., Renau-Piqueras J., Guerri C., 2003. Chronic ethanol consumption enhances interleukin-1-mediated signal transduction in rat liver and in cultured hepatocytes Alcohol Clin. Exp. Res. 27:1979–1986

    Article  PubMed  CAS  Google Scholar 

  24. Hoek J.B., Pastorino J.G., 2002. Ethanol, oxidative stress, and cytokine-induced liver cell injury Alcohol 27:63–68

    Article  PubMed  CAS  Google Scholar 

  25. Jokelainen K., Reinke L.A., Nanji A.A., 2001. NF-κB activation is associated with free radical generation and endotoxemia and precedes pathological liver injury in experimental alcoholic liver disease Cytokine 16:36–39

    PubMed  Article  CAS  Google Scholar 

  26. Wu D., Cederbaum A., 1996 Ethanol cytotoxicity to a transfected HepG2 cell line expressing human cytochrome P4502E1 J. Biol. Chem. 271:23914–23919

    Article  PubMed  CAS  Google Scholar 

  27. Román J., Colell A., Blasco C., Caballeria J., Parés A., Rodés J., Fernandez-Checa J.C., 1999. Differential role of ethanol and acetaldehyde in the induction of oxidative stress in HEP G2 cells: effect on transcription factors AP-1 and NF-κB Hepatology 30:1473–1480

    Article  PubMed  Google Scholar 

  28. Lee F.S., Hagler J., Chen J., Maniatis T., 1997. Activation of the IκBα kinase complex by MEKK1, a kinase of the JNK pathway Cell 88:213–222

    Article  PubMed  CAS  Google Scholar 

  29. Ninomiya-Tsuji J., Kishimoto K., Hiyama A., Inoue J.I., Cao Z., Matsumoto K., 1999. The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signaling pathway Nature 398:252–256

    Article  PubMed  CAS  Google Scholar 

  30. Zhao Q., Lee F.S., 1999. Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-κB through IκB kinase-α and IκB kinase-β J. Biol. Chem. 274:8355–8358

    Article  PubMed  CAS  Google Scholar 

  31. Anania F.A., Womack L., Jiang M., Saxena N.K., 2001. Aldehydes potentiate alpha(2)(I) collagen gene activity by JNK in hepatic stellate cells Free Radic. Biol. Med. 30:846–857

    Article  PubMed  CAS  Google Scholar 

  32. Casini A., Galli G., Salzano R., Ceni E., Franceschelli F., Rotella C.M., Surrenti C., 1994. Acetaldehyde induces c-fos and c-jun proto-oncogenes in fat-storing cell cultures through protein kinase C activation Alcohol Alcoholism 29:303–314

    PubMed  CAS  Google Scholar 

  33. Román J., Giménez A., Lluis J.M., Gassó M., Rubio M., Caballeria J., Pares A., Rodes J., Fernandez-Checa J.C., 2000. Enhanced DNA binding and activation of transcription factors NF-κB and AP-1 by acetaldehyde in HEPG2 cells J. Biol. Chem. 275:14684–14690

    Article  PubMed  Google Scholar 

  34. Auphan N., DiDonato J.A., Rosette C., Helmberg A., Karin M., 1995. Immunosuppression by glucocorticoids: inhibition of NF-κB activity through induction of IκB synthesis Science 270:286–290

    PubMed  Article  CAS  Google Scholar 

  35. Scheinman R.I., Cogswell P.C., Lofquist A.K., Baldwin A.J., 1995. Role of transcriptional activation of IκB-α in mediation of immunosuppression by glucocorticoids Science 270:283–286

    PubMed  Article  CAS  Google Scholar 

  36. Meyer S., Kohler N.G., Joly A., 1997. Cyclosporin A is a non-competitive inhibitor of proteasome activity and prevents NF-κB activation FEBS Lett. 413:354–358

    Article  PubMed  CAS  Google Scholar 

  37. Leung D.Y., Szefler S.J., 1998. New insights into steroid resistant asthma Pediatr. Allergy Immunol. 9:3–12

    PubMed  Article  CAS  Google Scholar 

  38. Ikram M., 1975. A review on the chemical and pharmacological aspects of genus Berberis Planta Med. 28:353–358

    PubMed  CAS  Google Scholar 

  39. Schmeller T., Latz-Bruning B., Wink M., 1997. Biochemical activities of berberine, palmaltine and sanguinarine mediating chemical defense against microorganisms and herbivores Phytochemistry 44:257–266

    Article  PubMed  CAS  Google Scholar 

  40. Kettmann V., Kosfalova D., Jantova S., Cernakova M., Drimal J., 2004. In vitro cytotoxicity of berberine against HeLa and L1210 cancer cell lines Pharmazie 59:548–551

    PubMed  CAS  Google Scholar 

  41. Mitani N., Murakami K., Yamaura T., Ikeda T., Saiki I., 2001. Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotropic implantation of Lewis lung carcinoma Cancer Lett. 165:35–42

    Article  PubMed  CAS  Google Scholar 

  42. Kuo C.L., Chi C.W., Liu T.Y., 2004. The anti-inflammatory potential of berberine in vitro and in vivo Cancer Lett. 203:127–137

    Article  PubMed  CAS  Google Scholar 

  43. Yasukawa K., Takido M., Ikekawa T., Shimada F., Takeuchi M., Nakagawa S., 1991. Relative inhibitory activity of berberine-type alkaloids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice Chem. Pharm. Bull 39:1462–1465

    PubMed  CAS  Google Scholar 

  44. Fukuda K., Hibiya Y., Mutoh M., Koshiji M., Akao S., Fujiwara H., 1999. Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells J. Enthopharmacol 66:227–233

    Article  CAS  Google Scholar 

  45. Lee D.U., Kang Y.J., Park M.K., Lee Y.S., Seo H.G., Kim T.S., Kim C.H., Chang K.C., 2003. Effects of 13-alkyl-substituted berberine alkaloids on the expression of COX-II, TNF-α, iNOS, and IL-12 production in LPS-stimulated macrophages Life Sci. 73:1401–1412

    Article  PubMed  CAS  Google Scholar 

  46. Shemon A.N., Sluyter R., Conigrave A.D., Wiley J.S., 2004. Chelerythrine and other benzophenanthridine alkaloids block the human P2X7 receptor Br. J. Pharmacol 142:1015–1019

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from National Science Council and China Medical University, Taiwan, ROC.

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Affiliations

  1. Graduate Institute of Medical Science, China Medical University, Taichung 404, Taiwan

    Chien-Yun Hsiang & Shih-Lu Wu

  2. Molecular Biology Laboratory, Graduate Institute of Chinese Medical Science, China Medical University, 91 Hsueh-Shih Road, Taichung 404, Taiwan

    Shin-Ei Cheng & Tin-Yun Ho

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  1. Chien-Yun Hsiang
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  2. Shih-Lu Wu
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Correspondence to Tin-Yun Ho.

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Hsiang, CY., Wu, SL., Cheng, SE. et al. Acetaldehyde-induced interleukin-1β and tumor necrosis factor-α production is inhibited by berberine through nuclear factor-κB signaling pathway in HepG2 cells. J Biomed Sci 12, 791–801 (2005). https://doi.org/10.1007/s11373-005-9003-4

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  • DOI: https://doi.org/10.1007/s11373-005-9003-4

Keywords

  • acetaldehyde
  • alcoholic liver disease
  • berberine
  • cytokine
  • nuclear factor-κB