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Inhibition of TNFα-induced interleukin-6 gene expression by barley (Hordeum vulgare) ethanol extract in BV-2 microglia

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Abstract

Background

Inflammation in the central nervous system is closely associated with pathological neurodegenerative diseases as well as psychiatric disorders. Prolonged activation of microglia can produce many inflammatory mediators, which may result in pathological neurotoxic side effects. Interleukin (IL)-6 serves as a hallmark of the injured brain.

Objective

Whole grains are known to contain many bioactive components. However, little information is available about anti-neuroinflammatory effects of grains in the CNS. This study aims to investigate the effect of Hordeum vulgare ethanol extract (HVE) on the suppression of IL-6 expression in BV2 microglia.

Methods

Inhibitory effects of HVE on IL-6 expression were analyzed by immunoblot anaysis, immunofluoresce microscopic analysis, reverse transcription-polymerase chain reaction, and luciferase promoter reporter assay.

Results

HVE inhibited TNFα-induced phosphorylation of IKKα/β, IκB, and p65/RelA NF-κB. TNFα-induced IL-6 mRNA expression and promoter activity were reduced by HVE. Point mutation of NF-κB-binding site within the IL-6 gene promoter abolished TNFα-induced reporter activity, whereas exogenous expression of p65 NF-κB enhanced IL-6 promoter activity.

Conclusion

NF-κB-binding site within the IL-6 promoter region is a HVE target element involved in the inhibition of TNFα-induced IL-6 gene transcription. HVE inhibits TNFα-induced IL-6 expression via suppression of NF-κB signaling in BV2 microglial cells.

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References

  • Baccam M, Woo SY, Vinson C, Bishop GA (2003) CD40-mediated transcriptional regulation of the IL-6 gene in B lymphocytes: involvement of NF-kappa B, AP-1, and C/EBP. J Immunol 170:3099–3108

    Article  CAS  PubMed  Google Scholar 

  • Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9:361–371

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ, Karin M (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:1066–1071

    Article  CAS  PubMed  Google Scholar 

  • Becher B, Spath S, Goverman J (2017) Cytokine networks in neuroinflammation. Nat Rev Immunol 17:49–59

    Article  CAS  PubMed  Google Scholar 

  • Bhakar AL, Tannis LL, Zeindler C, Russo MP, Jobin C, Park DS, MacPherson S, Barker PA (2002) Constitutive nuclear factor-kappa B activity is required for central neuron survival. J Neurosci 22:8466–8475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell IL, Erta M, Lim SL, Frausto R, May U, Rose-John S, Scheller J, Hidalgo J (2014) Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. J Neurosci 34:2503–2513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen LF, Greene WC (2004) Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 5:392–401

    Article  CAS  PubMed  Google Scholar 

  • Choi KC, Hwang JM, Bang SJ, Son YO, Kim BT, Kim DH, Lee SA, Chae M, Kim DH, Lee JC (2013) Methanol extract of the aerial parts of barley (Hordeum vulgare) suppresses lipopolysaccharide-induced inflammatory responses in vitro and in vivo. Pharm Biol 51:1066–1076

    Article  CAS  PubMed  Google Scholar 

  • Dendorfer U, Oettgen P, Libermann TA (1994) Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol Cell Biol 14:4443–4454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dobos N, Korf J, Luiten PG, Eisel UL (2010) Neuroinflammation in Alzheimer’s disease and major depression. Biol Psychiatry 67:503–504

    Article  PubMed  Google Scholar 

  • Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A (2002) Neuroinflammation in Alzheimer’s disease and prion disease. Glia 40:232–239

    Article  CAS  PubMed  Google Scholar 

  • Ferreres F, Krskova Z, Goncalves RF, Valentao P, Pereira JA, Dusek J, Martin J, Andrade PB (2009) Free water-soluble phenolics profiling in barley (Hordeum vulgare L.). J Agric Food Chem 57:2405–2409

    Article  CAS  PubMed  Google Scholar 

  • Frost JL, Schafer DP (2016) Microglia: architects of the developing nervous system. Trends Cell Biol 26:587–597

    Article  PubMed  PubMed Central  Google Scholar 

  • Garbers C, Aparicio-Siegmund S, Rose-John S (2015) The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr Opin Immunol 34:75–82

    Article  CAS  PubMed  Google Scholar 

  • Goldsmith DR, Rapaport MH, Miller BJ (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 21:1696–1709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hernanz D, Nunez V, Sancho AI, Faulds CB, Williamson G, Bartolome B, Gomez-Cordoves C (2001) Hydroxycinnamic acids and ferulic acid dehydrodimers in barley and processed barley. J Agric Food Chem 49:4884–4888

    Article  CAS  PubMed  Google Scholar 

  • Hoesel B, Schmid JA (2013) The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 12:86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeon S, Kim SH, Shin SY, Lee YH (2018) Clozapine reduces Toll-like receptor 4/NF-kappaB-mediated inflammatory responses through inhibition of calcium/calmodulin-dependent Akt activation in microglia. Prog Neuropsychopharmacol Biol Psychiatry. 81:477–487. https://doi.org/10.1016/j.pnpbp.2017.04.012

    Article  CAS  PubMed  Google Scholar 

  • Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436

    Article  CAS  PubMed  Google Scholar 

  • Kim YK, Na KS, Myint AM, Leonard BE (2016) The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuropsychopharmacol Biol Psychiatry 64:277–284

    Article  CAS  PubMed  Google Scholar 

  • Kirch DG (1993) Infection and autoimmunity as etiologic factors in schizophrenia: a review and reappraisal. Schizophr Bull 19:355–370

    Article  CAS  PubMed  Google Scholar 

  • Kuno R, Wang J, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A (2005) Autocrine activation of microglia by tumor necrosis factor-alpha. J Neuroimmunol 162:89–96

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2:725–734

    Article  CAS  PubMed  Google Scholar 

  • Libermann TA, Baltimore D (1990) Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 10:2327–2334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo JL, Kamata H, Karin M (2005) IKK/NF-kappaB signaling: balancing life and death–a new approach to cancer therapy. J Clin Invest 115:2625–2632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madhujith T, Shahidi F (2007) Antioxidative and antiproliferative properties of selected barley (Hordeum vulgarae L.) cultivars and their potential for inhibition of low-density lipoprotein (LDL) cholesterol oxidation. J Agric Food Chem 55:5018–5024

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP, Camandola S (2001) NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107:247–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minghetti L (2005) Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 18:315–321

    Article  CAS  PubMed  Google Scholar 

  • Nimmo AJ, Vink R (2009) Recent patents in CNS drug discovery: the management of inflammation in the central nervous system. Recent Pat CNS Drug Discov 4:86–95

    Article  CAS  PubMed  Google Scholar 

  • O’Neill LA, Kaltschmidt C (1997) NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci 20:252–258

    Article  PubMed  Google Scholar 

  • Okamoto T, Sanda T, Asamitsu K (2007) NF-kappa B signaling and carcinogenesis. Curr Pharm Des 13:447–462

    Article  CAS  PubMed  Google Scholar 

  • Okarter N, Liu RH (2010) Health benefits of whole grain phytochemicals. Crit Rev Food Sci Nutr 50:193–208

    Article  CAS  PubMed  Google Scholar 

  • Peña-Altamira E, Prati F, Massenzio F, Virgili M, Contestabile A, Bolognesi ML, Monti B (2016) Changing paradigm to target microglia in neurodegenerative diseases: from anti-inflammatory strategy to active immunomodulation. Expert Opin Ther Targets 20:627–640

    Article  CAS  PubMed  Google Scholar 

  • Quinde-Axtell Z, Baik BK (2006) Phenolic compounds of barley grain and their implication in food product discoloration. J Agric Food Chem 54:9978–9984

    Article  CAS  PubMed  Google Scholar 

  • Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9:429–439

    Article  CAS  PubMed  Google Scholar 

  • Rothaug M, Becker-Pauly C, Rose-John S (2016) The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta 1863:1218–1227

    Article  CAS  PubMed  Google Scholar 

  • Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W (1999) IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J Biol Chem 274:30353–30356

    Article  CAS  PubMed  Google Scholar 

  • Shih RH, Wang CY, Yang CM (2015) NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 8:77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin SY, Kim CG, Jung YJ, Lim Y, Lee YH (2016) The UPR inducer DPP23 inhibits the metastatic potential of MDA-MB-231 human breast cancer cells by targeting the Akt-IKK-NF-kappaB-MMP-9 axis. Sci Rep 6:34134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin SY, Kim HW, Jang HH, Hwang YJ, Choe JS, Lim Y, Kim JB, Lee YH (2017) Gamma-Oryzanol-rich black rice bran extract enhances the innate immune response. J Med Food 20:855–863

    Article  CAS  PubMed  Google Scholar 

  • Singh A, Sharma S (2017) Bioactive components and functional properties of biologically activated cereal grains: a bibliographic review. Crit Rev Food Sci Nutr 57:3051–3071

    Article  CAS  PubMed  Google Scholar 

  • Singhal G, Baune BT (2017) Microglia: an interface between the loss of neuroplasticity and depression. Front Cell Neurosci 11:270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Invest 107:7–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6:a016295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang SH, Gangidine M, Pritts TA, Goodman MD, Lentsch AB (2013) Interleukin 6 mediates neuroinflammation and motor coordination deficits after mild traumatic brain injury and brief hypoxia in mice. Shock 40:471–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Konkuk University Research Support Program in 2015. JC, JK, DYM, and EJ were supported by Konkuk University Researcher Fund in 2017.

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Authors and Affiliations

  1. Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul, 05029, Republic of Korea

    Jihye Choi, Juhwan Kim, Dong Yeong Min, Euitaek Jung, Soon Young Shin & Young Han Lee

  2. Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, 05029, Republic of Korea

    Yoongho Lim

  3. Cancer and Metabolism Institute, Konkuk University, Seoul, 05029, Republic of Korea

    Soon Young Shin & Young Han Lee

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  1. Jihye Choi
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  2. Juhwan Kim
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  4. Euitaek Jung
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Contributions

SYS, YL, and YHL designed research; JC, JK, DYM, and EJ performed experiments. SYS and YHL wrote the paper.

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Correspondence to Young Han Lee.

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Choi, J., Kim, J., Min, D.Y. et al. Inhibition of TNFα-induced interleukin-6 gene expression by barley (Hordeum vulgare) ethanol extract in BV-2 microglia. Genes Genom 41, 557–566 (2019). https://doi.org/10.1007/s13258-018-00781-8

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  • DOI: https://doi.org/10.1007/s13258-018-00781-8

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