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Folic acid inhibits lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages by suppressing MAPKs and NF-κB activation

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Abstract

Objective

The aim of the present study was to investigate the effects of folic acid on the inflammatory responses to lipopolysaccharide (LPS) in RAW264.7 cells and the signal transduction pathways involved.

Methods

RAW264.7 macrophages were used. The production of nitric oxide (NO) was determined by the Griess test. The protein levels and mRNA expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) were determined by ELISA and RT-PCR, respectively. The phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear nuclear factor-kappa B (NF-κB) p65 protein were analyzed by Western blotting.

Results

Folic acid inhibited LPS-induced production of NO, TNF-α and IL-1β with decreased mRNAs of inducible nitric oxide synthase (iNOS), TNF-α and IL-1β. Further study showed that folic acid inhibited the LPS-induced phosphorylation of MAPKs and the nuclear translocation of NF-κB.

Conclusion

Folic acid inhibits the inflammatory response of RAW 264.7 cells to LPS through inhibiting the MAPKs and NF-κB pathways.

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References

  1. Iyer R, Tomar SK. Folate: a functional food constituent. J Food Sci. 2009;74:R114–22.

    Article  PubMed  CAS  Google Scholar 

  2. Hoffbrand AV, Weir DG. The history of folic acid. Br J Haematol. 2001;113:579–89.

    Article  PubMed  CAS  Google Scholar 

  3. Scott JM, Weir DG. Folic acid, homocysteine and one-carbon metabolism: a review of the essential biochemistry. J Cardiovasc Risk. 1998;5:223–7.

    Article  PubMed  CAS  Google Scholar 

  4. Wani NA, Hamid A, Kaur J. Folate status in various pathophysiological conditions. IUBMB Life. 2008;60:834–42.

    Article  PubMed  Google Scholar 

  5. Gori T, Burstein JM, Ahmed S, Miner SE, Al-Hesayen A, Kelly S, et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation. 2001;104:1119–23.

    Article  PubMed  CAS  Google Scholar 

  6. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007;369:1876–82.

    Article  PubMed  CAS  Google Scholar 

  7. Magni E, Bianchetti A, Rozzini R, Trabucchi M. Influence of nutritional intake on 6-year mortality in an Italian elderly population. J Nutr Elder. 1994;13:25–34.

    Article  PubMed  CAS  Google Scholar 

  8. Imamura A, Murakami R, Takahashi R, Cheng XW, Numaguchi Y, Murohara T, et al. Low folate levels may be an atherogenic factor regardless of homocysteine levels in young healthy nonsmokers. Metabolism. 2010;59:728–33.

    Article  PubMed  CAS  Google Scholar 

  9. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567–77.

    Article  PubMed  CAS  Google Scholar 

  10. McCarty MF, Barroso-Aranda J, Contreras F. High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals–clinical potential in inflammatory disorders. Med Hypotheses. 2009;73:824–34.

    Article  PubMed  CAS  Google Scholar 

  11. Title LM, Ur E, Giddens K, McQueen MJ, Nassar BA. Folic acid improves endothelial dysfunction in type 2 diabetes––an effect independent of homocysteine-lowering. Vasc Med. 2006;11:101–9.

    Article  PubMed  Google Scholar 

  12. Solini A, Santini E, Ferrannini E. Effect of short-term folic acid supplementation on insulin sensitivity and inflammatory markers in overweight subjects. Int J Obes (Lond). 2006;30:1197–202.

    Article  CAS  Google Scholar 

  13. Chiarello PG, Penaforte FR, Japur CC, Souza CD, Vannucchi H, Troncon LE. Increased folate intake with no changes in serum homocysteine and decreased levels of C-reactive protein in patients with inflammatory bowel diseases. Dig Dis Sci. 2009;54:627–33.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang R, Ma J, Xia M, Zhu H, Ling W. Mild hyperhomocysteinemia induced by feeding rats diets rich in methionine or deficient in folate promotes early atherosclerotic inflammatory processes. J Nutr. 2004;134:825–30.

    PubMed  CAS  Google Scholar 

  15. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–74.

    Article  PubMed  CAS  Google Scholar 

  16. Laskin DL, Pendino KJ. Macrophages and inflammatory mediators in tissue injury. Annu Rev Pharmacol Toxicol. 1995;35:655–77.

    Article  PubMed  CAS  Google Scholar 

  17. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.

    Article  PubMed  CAS  Google Scholar 

  18. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982;126:131–8.

    Article  PubMed  CAS  Google Scholar 

  19. Carter AB, Knudtson KL, Monick MM, Hunninghake GW. The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). J Biol Chem. 1999;274:30858–63.

    Article  PubMed  CAS  Google Scholar 

  20. Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H, et al. Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc Natl Acad Sci USA. 1998;95:3537–42.

    Article  PubMed  CAS  Google Scholar 

  21. Yea SS, Yang KH, Kaminski NE. Role of nuclear factor of activated T-cells and activator protein-1 in the inhibition of interleukin-2 gene transcription by cannabinol in EL4 T-cells. J Pharmacol Exp Ther. 2000;292:597–605.

    PubMed  CAS  Google Scholar 

  22. Korhonen R, Lahti A, Kankaanranta H, Moilanen E. Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy. 2005;4:471–9.

    Article  PubMed  CAS  Google Scholar 

  23. Detmers PA, Hernandez M, Mudgett J, Hassing H, Burton C, Mundt S, et al. Deficiency in inducible nitric oxide synthase results in reduced atherosclerosis in apolipoprotein E-deficient mice. J Immunol. 2000;165:3430–5.

    PubMed  CAS  Google Scholar 

  24. Beutler B. TNF, immunity and inflammatory disease: lessons of the past decade. J Investig Med. 1995;43:227–35.

    PubMed  CAS  Google Scholar 

  25. Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010;6:232–41.

    Article  PubMed  CAS  Google Scholar 

  26. Bluthgen N, Legewie S. Systems analysis of MAPK signal transduction. Essays Biochem. 2008;45:95–107.

    Article  PubMed  Google Scholar 

  27. Turjanski AG, Vaque JP, Gutkind JS. MAP kinases and the control of nuclear events. Oncogene. 2007;26:3240–53.

    Article  PubMed  CAS  Google Scholar 

  28. Ghosh S. Regulation of inducible gene expression by the transcription factor NF-kappaB. Immunol Res. 1999;19:183–9.

    Article  PubMed  CAS  Google Scholar 

  29. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev. 2004;18:2195–224.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 30872101).

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Correspondence to Jing Ma.

Additional information

Responsible Editor: Liwu Li.

D. Feng and Y. Zhou are contributed equally to this work.

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Feng, D., Zhou, Y., Xia, M. et al. Folic acid inhibits lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages by suppressing MAPKs and NF-κB activation. Inflamm. Res. 60, 817–822 (2011). https://doi.org/10.1007/s00011-011-0337-2

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  • DOI: https://doi.org/10.1007/s00011-011-0337-2

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