Skip to main content

Advertisement

Log in

Cyanidin-3-O-β-glucoside inhibits LPS-induced expression of inflammatory mediators through decreasing IκBα phosphorylation in THP-1 cells

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

As a common phytochemical, cyanidin 3-O-β-glucoside (C3G) has a role in inhibiting inflammatory mediators; however, its mechanism of action remains unclear. The purpose of this study was to explore the effect of C3G on lipopolysaccharide (LPS)-stimulated TNFα and IL-6 expression in the human monocyte/macrophage cell line THP-1, and to explore the mechanisms involved.

Methods

Differentiated THP-1 cells were treated with different concentrations of C3G (0.005, 0.05, 0.5,10 μM) in the absence or presence of 1 ng/mL LPS. mRNA expression levels were detected by real time PCR, and secretion of TNFα and IL-6, phosphorylated IκBα, and nuclear factor-kappa B (NF-κB) P65 were monitored by ELISA or Western blotting analysis. The role of an inhibitor of IκBα phosphorylation, BAY 11-7082, in C3G inhibition of LPS-induced cytokines expression was investigated.

Results

C3G (0.05–0.5 μM) treatment significantly inhibited LPS-stimulated TNFα and IL-6 mRNA expression and secretion of these proteins by THP-1 cells. Phosphorylation of IκBα and NF-κB nuclear translocation could be blocked by 0.5 μM C3G. BAY 11-7082 treatment abolished C3G-induced reduction of TNFα and IL-6.

Conclusion

Our results suggest that C3G exerts its anti-inflammatory effect through inhibiting IκBα phosphorylation, thereby suppressing NF-κB activity in THP-1 cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.

    Article  CAS  PubMed  Google Scholar 

  2. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.

    CAS  PubMed  Google Scholar 

  3. Spah F. Inflammation in atherosclerosis and psoriasis: common pathogenic mechanisms and the potential for an integrated treatment approach. Br J Dermatol. 2008;159(Suppl 2):10–7.

    Article  PubMed  Google Scholar 

  4. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

    CAS  PubMed  Google Scholar 

  5. Hsieh PS. Inflammatory change of fatty liver induced by intraportal low-dose lipopolysaccharide infusion deteriorates pancreatic insulin secretion in fructose-induced insulin-resistant rats. Liver Int. 2008;28:1167–75.

    CAS  PubMed  Google Scholar 

  6. Miller MA, McTernan PG, Harte AL, Silva NF, Strazzullo P, Alberti KG, et al. Ethnic and sex differences in circulating endotoxin levels: A novel marker of atherosclerotic and cardiovascular risk in a British multi-ethnic population. Atherosclerosis. 2009;203:494–502.

    Article  CAS  PubMed  Google Scholar 

  7. Yamashita A, Soga Y, Iwamoto Y, Yoshizawa S, Iwata H, Kokeguchi S, et al. Macrophage–adipocyte interaction: marked interleukin-6 production by lipopolysaccharide. Obesity. 2007;15:2549–52.

    Article  CAS  PubMed  Google Scholar 

  8. Odrowaz-Sypniewska G. Markers of pro-inflammatory and pro-thrombotic state in the diagnosis of metabolic syndrome. Adv Med Sci. 2007;52:246–50.

    CAS  PubMed  Google Scholar 

  9. Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:367–77.

    Article  CAS  PubMed  Google Scholar 

  10. Eder K, Baffy N, Falus A, Fulop AK. The major inflammatory mediator interleukin-6 and obesity. Inflamm Res. 2009;58:727–36.

    Article  CAS  PubMed  Google Scholar 

  11. Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol. 2006;26:3071–84.

    Article  CAS  PubMed  Google Scholar 

  12. Seimon T, Tabas I. Mechanisms and consequences of macrophage apoptosis in atherosclerosis. J Lipid Res. 2009;50(Suppl):S382–7.

    Article  PubMed  Google Scholar 

  13. Zhang H, Park Y, Wu J, Chen X, Lee S, Yang J, et al. Role of TNF-alpha in vascular dysfunction. Clin Sci (Lond). 2009;116:219–30.

    Article  CAS  Google Scholar 

  14. Popa C, Netea MG, Radstake T, Van der Meer JW, Stalenhoef AF, van Riel PL, et al. Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann Rheum Dis. 2005;64:303–5.

    Article  CAS  PubMed  Google Scholar 

  15. Hu SW, Bevona C, Winterfield L, Qureshi AA, Li VW. Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. Arch Dermatol. 2009;145:437–9.

    Article  CAS  PubMed  Google Scholar 

  16. Huvers FC, Popa C, Netea MG, van den Hoogen FH, Tack CJ. Improved insulin sensitivity by anti-TNFalpha antibody treatment in patients with rheumatic diseases. Ann Rheum Dis. 2007;66:558–9.

    Article  CAS  PubMed  Google Scholar 

  17. Ahn KS, Aggarwal BB. Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann N Y Acad Sci. 2005;1056:218–33.

    Article  CAS  PubMed  Google Scholar 

  18. Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor-kappaB: its role in health and disease. J Mol Med. 2004;82:434–48.

    Article  CAS  PubMed  Google Scholar 

  19. Galvano F, La Fauci L, Vitaglione P, Fogliano V, Vanella L, Felgines C. Bioavailability, antioxidant and biological properties of the natural free-radical scavengers cyanidin and related glycosides. Ann Ist Super Sanita. 2007;43:382–93.

    CAS  PubMed  Google Scholar 

  20. Sasaki R, Nishimura N, Hoshino H, Isa Y, Kadowaki M, Ichi T, et al. Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice. Biochem Pharmacol. 2007;74:1619–27.

    Article  CAS  PubMed  Google Scholar 

  21. Ding M, Feng R, Wang SY, Bowman L, Lu Y, Qian Y, et al. Cyanidin-3-glucoside, a natural product derived from blackberry, exhibits chemopreventive and chemotherapeutic activity. J Biol Chem. 2006;281:17359–68.

    Article  CAS  PubMed  Google Scholar 

  22. Kang TH, Hur JY, Kim HB, Ryu JH, Kim SY. Neuroprotective effects of the cyanidin-3-O-beta-d-glucopyranoside isolated from mulberry fruit against cerebral ischemia. Neurosci Lett. 2006;391:122–6.

    Article  CAS  PubMed  Google Scholar 

  23. Tarozzi A, Morroni F, Hrelia S, Angeloni C, Marchesi A, Cantelli-Forti G, et al. Neuroprotective effects of anthocyanins and their in vivo metabolites in SH-SY5Y cells. Neurosci Lett. 2007;424:36–40.

    Article  CAS  PubMed  Google Scholar 

  24. Tsuda T, Horio F, Uchida K, Aoki H, Osawa T. Dietary cyanidin 3-O-beta-d-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice. J Nutr. 2003;133:2125–30.

    CAS  PubMed  Google Scholar 

  25. Duthie SJ. Berry phytochemicals, genomic stability and cancer: evidence for chemoprotection at several stages in the carcinogenic process. Mol Nutr Food Res. 2007;51:665–74.

    Article  CAS  PubMed  Google Scholar 

  26. Matsunaga N, Imai S, Inokuchi Y, Shimazawa M, Yokota S, Araki Y, et al. Bilberry and its main constituents have neuroprotective effects against retinal neuronal damage in vitro and in vivo. Mol Nutr Food Res. 2009;53:869–77.

    Article  CAS  PubMed  Google Scholar 

  27. Herath HM, Takano-Ishikawa Y, Yamaki K. Inhibitory effect of some flavonoids on tumor necrosis factor-alpha production in lipopolysaccharide-stimulated mouse macrophage cell line J774.1. J Med Food. 2003;6:365–70.

    Article  PubMed  Google Scholar 

  28. Jin XH, Ohgami K, Shiratori K, Suzuki Y, Koyama Y, Yoshida K, et al. Effects of blue honeysuckle (Lonicera caerulea L.) extract on lipopolysaccharide-induced inflammation in vitro and in vivo. Exp Eye Res. 2006;82:860–7.

    Article  CAS  PubMed  Google Scholar 

  29. Wang Q, Xia M, Liu C, Guo H, Ye Q, Hu Y, et al. Cyanidin-3-O-beta-glucoside inhibits iNOS and COX-2 expression by inducing liver X receptor alpha activation in THP-1 macrophages. Life Sci. 2008;83:176–84.

    Article  CAS  PubMed  Google Scholar 

  30. Pierce JW, Schoenleber R, Jesmok G, Best J, Moore SA, Collins T, et al. Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J Biol Chem. 1997;272:21096–103.

    Article  CAS  PubMed  Google Scholar 

  31. Jeffes EW 3rd, McCullough JL, Pittelkow MR, McCormick A, Almanzor J, Liu G, et al. Methotrexate therapy of psoriasis: differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and growth-inhibitory effects of methotrexate. J Invest Dermatol. 1995;104:183–8.

    Article  PubMed  Google Scholar 

  32. Fedorov SN, Makarieva TN, Guzii AG, Shubina LK, Kwak JY, Stonik VA. Marine two-headed sphingolipid-like compound rhizochalin inhibits EGF-induced transformation of JB6 P(+) Cl41 cells. Lipids. 2009;44:777–85.

    Article  CAS  PubMed  Google Scholar 

  33. Prior RL, Wu X. Anthocyanins: structural characteristics that result in unique metabolic patterns and biological activities. Free Radic Res. 2006;40:1014–28.

    Article  CAS  PubMed  Google Scholar 

  34. Collart MA, Baeuerle P, Vassalli P. Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol Cell Biol. 1990;10:1498–506.

    CAS  PubMed  Google Scholar 

  35. Deshpande R, Khalili H, Pergolizzi RG, Michael SD, Chang MD. Estradiol down-regulates LPS-induced cytokine production and NFkB activation in murine macrophages. Am J Reprod Immunol. 1997;38:46–54.

    CAS  PubMed  Google Scholar 

  36. Galien R, Evans HF, Garcia T. Involvement of CCAAT/enhancer-binding protein and nuclear factor-kappa B binding sites in interleukin-6 promoter inhibition by estrogens. Mol Endocrinol. 1996;10:713–22.

    Article  CAS  PubMed  Google Scholar 

  37. Dendorfer U, Oettgen P, Libermann TA. Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol Cell Biol. 1994;14:4443–54.

    CAS  PubMed  Google Scholar 

  38. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997;388:548–54.

    Article  CAS  PubMed  Google Scholar 

  39. Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, et al. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science. 1997;278:860–6.

    Article  CAS  PubMed  Google Scholar 

  40. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell. 1997;91:243–52.

    Article  CAS  PubMed  Google Scholar 

  41. Le Bail O, Schmidt-Ullrich R, Israel A. Promoter analysis of the gene encoding the I kappa B-alpha/MAD3 inhibitor of NF-kappa B: positive regulation by members of the rel/NF-kappa B family. EMBO J. 1993;12:5043–9.

    CAS  PubMed  Google Scholar 

  42. Ito CY, Adey N, Bautch VL, Baldwin AS Jr. Structure and evolution of the human IKBA gene. Genomics. 1995;29:490–5.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Drs. Dayong Wu and Fu Shang in Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, USA for technical advice. This work was a joint research training program supported by the National Natural Science Foundation of China (Grant No. 30730079), and the U.S. Department of Agriculture (Grant No. 1950-51000-064).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wenhua Ling or Xiang-Dong Wang.

Additional information

Responsible Editor: G. Wallace.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Lian, F., Zhu, Y. et al. Cyanidin-3-O-β-glucoside inhibits LPS-induced expression of inflammatory mediators through decreasing IκBα phosphorylation in THP-1 cells. Inflamm. Res. 59, 723–730 (2010). https://doi.org/10.1007/s00011-010-0183-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-010-0183-7

Keywords

Navigation