Skip to main content

Advertisement

SpringerLink
Log in

Brefeldin A reduces tumor necrosis factor-α-stimulated production of inflammatory mediators by suppressing the Akt, mTOR, and NF-κB pathways in human keratinocytes

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Keratinocytes may play an important role in the pathogenesis of inflammatory skin diseases. Brefeldin A has been shown to attenuate the production and secretion of chemical mediators involved in inflammation and immune responses. However, the effect of brefeldin A on the TNF-α-stimulated production of inflammatory mediators in keratinocytes has not been studied. We investigated the effect of brefeldin A on the TNF-α-stimulated production of inflammatory mediators using HaCaT cells and primary keratinocytes in relation to the Akt, mTOR, and NF-κB pathways, which regulates the transcription genes involved in immune and inflammatory responses. Brefeldin A, Akt inhibitor, Bay 11-7085 (an inhibitor of NF-κB activation), and rapamycin (mTOR inhibitor) inhibited the TNF-α-stimulated productions of inflammatory mediators, and activations of Akt, mTOR, and NF-κB in keratinocytes. The results show that brefeldin A appears to attenuate TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of the Akt, mTOR, and NF-κB pathways.

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

Access this article

Log in via an institution

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
Fig. 5

Similar content being viewed by others

References

  • Aggarwal BB, Shishodia S, Takada Y, Jackson-Bernitsas D, Ahn KS, Sethi G, Ichikawa H (2006) TNF blockade: an inflammatory issue. Ernst Schering Res Found Workshop 56:161–186

    Article  PubMed  Google Scholar 

  • Angelini F, Di Matteo G, Balestrero S, Brunetti E, Mancino G, Rossi P, Galli E (2007) NFκB activity is increased in peripheral blood mononuclear cells of children affected by atopic and non-atopic eczema. Int J Immunopathol Pharmacol 20:59–67

    CAS  PubMed  Google Scholar 

  • Brotas AM, Cunha JM, Lago EH, Machado CC, Carneiro SC (2012) Tumor necrosis factor-α and the cytokine network in psoriasis. An Bras Dermatol 87:673–681

    Article  PubMed  Google Scholar 

  • Diamant G, Dikstein R (2013) Transcriptional control by NF-κB: elongation in focus. Biochim Biophys Acta 1829:937–945

    Article  CAS  PubMed  Google Scholar 

  • Enk R, Ehehalt R, Graham JE, Bierhaus A, Remppis A, Greten HJ (2007) Differential effect of Rhizoma coptidis and its main alkaloid compound berberine on TNF-α induced NFκB translocation in human keratinocytes. J Ethnopharmacol 109:170–175

    Article  CAS  PubMed  Google Scholar 

  • Faurschou A (2010) Role of tumor necrosis factor-α in the regulation of keratinocyte cell cycle and DNA repair after ultraviolet-B radiation. Dan Med Bull 57:B4179

    PubMed  Google Scholar 

  • Faurschou A, Gniadecki R, Calay D, Wulf HC (2008) TNF-α impairs the S-G2/M cell cycle checkpoint and cyclobutane pyrimidine dimer repair in premalignant skin cells: role of the PI3K-Akt pathway. J Invest Dermatol 128:2069–2077

    Article  CAS  PubMed  Google Scholar 

  • Ghosh S, Hayden MS (2008) New regulators of NF-κB in inflammation. Nat Rev Immunol 8:837–848

    Article  CAS  PubMed  Google Scholar 

  • Gloire G, Legrand-Poels S, Piette J (2006) NF-κB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72:1493–1505

    Article  CAS  PubMed  Google Scholar 

  • Hoermannsperger G, Clavel T, Hoffmann M, Reiff C, Kelly D, Loh G, Blaut M, Hölzlwimmer G, Laschinger M, Haller D (2009) Post-translational inhibition of IP-10 secretion in IEC by probiotic bacteria: impact on chronic inflammation. PLoS ONE 4(2):e4365

    Article  PubMed  Google Scholar 

  • Incorvaia C, Frati F, Verna N, D’Alò S, Motolese A, Pucci S (2008) Allergy and the skin. Clin Exp Immunol Suppl 1:27–29

    Article  Google Scholar 

  • Islam SA, Luster AD (2012) T cell homing to epithelial barriers in allergic disease. Nat Med 18:705–715

    Article  CAS  PubMed  Google Scholar 

  • Kim JE, Kim BJ, Jeong MS, Seo SJ, Kim MN, Hong CK, Ro BI (2005) Expression and modulation of LL-37 in normal human keratinocytes, HaCaT cells and inflammatory skin diseases. J Korean Med Sci 20:649–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koyama Y, Suzuki T, Kajiya A, Isemura M (2005) Stimulation of IL-8 production by Aralia cordate lectin in human colon carcinoma Caco-2 cells. Biosci Biotechnol Biochem 69:202–205

    Article  CAS  PubMed  Google Scholar 

  • Kwak JH, Jung JK, Lee H (2011) Nuclear factor-κ B inhibitors; a patent review (2006–2010). Expert Opin Ther Pat 21:1897–1910

    Article  CAS  PubMed  Google Scholar 

  • Lee CS, Jeong EB, Kim YJ, Lee MS, Seo SJ, Park KH, Lee MW (2013) Quercetin-3-O-(2″-galloyl)-α-l-rhamnopyranoside inhibits TNF-α-activated NF-κB-induced inflammatory mediator production by suppressing ERK activation. Int Immunopharmacol 16:481–487

    Article  CAS  PubMed  Google Scholar 

  • Li J, Li J, Yue Y, Hu Y, Cheng W, Liu R, Pan X, Zhang P (2014) Genistein suppresses tumor necrosis factor α-induced inflammation via modulating reactive oxygen species/Akt/nuclear factor κB and adenosine monophosphate-activated protein kinase signal pathways in human synoviocyte MH7A cells. Drug Des Devel Ther 8:315–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mazza J, Rossi A, Weinberg JM (2010) Innovative uses of tumor necrosis factor α inhibitors. Dermatol Clin 28:559–575

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Murakawa M, Yamaoka K, Tanaka Y, Fukuda Y (2006) Involvement of tumor necrosis factor (TNF)-α in phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin edema in mice. Biochem Pharmacol 71:1331–1336

    Article  CAS  PubMed  Google Scholar 

  • Napetschnig J, Wu H (2013) Molecular basis of NF-κB signaling. Annu Rev Biophys 42:443–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Netsch MI, Gutmann H, Aydogan C, Drewe J (2006) Green tea extract induces interleukin-8 (IL-8) mRNA and protein expression but specifically inhibits IL-8 secretion in caco-2 cells. Planta Med 72:697–702

    Article  CAS  PubMed  Google Scholar 

  • Neves JS, Perez SA, Spencer LA, Melo RC, Reynolds L, Ghiran I, Mahmudi-Azer S, Odemuyiwa SO, Dvorak AM, Moqbel R, Weller PF (2008) Eosinophil granules function extracellularly as receptor-mediated secretory organelles. Proc Natl Acad Sci U S A 105:18478–18483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ouyang S, Hsuchou H, Kastin AJ, Pan W (2013) TNF stimulates nuclear export and secretion of IL-15 by acting on CRM1 and ARF6. PLoS ONE 8:e69356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park S, Regmi SC, Park SY, Lee EK, Chang JH, Ku SK, Kim DH, Kim JA (2014) Protective effect of 7-O-succinyl macrolactin A against intestinal inflammation is mediated through PI3-kinase/Akt/mTOR and NF-κB signaling pathways. Eur J Pharmacol 735C:184–192

    Article  Google Scholar 

  • Pastore S, Mascia F, Girolomoni G (2006) The contribution of keratinocytes to the pathogenesis of atopic dermatitis. Eur J Dermatol 16:125–131

    CAS  PubMed  Google Scholar 

  • Rebholz B, Haase I, Eckelt B, Paxian S, Flaig MJ, Ghoreschi K, Nedospasov SA, Mailhammer R, Debey-Pascher S, Schultze JL, Weindl G, Förster I, Huss R, Stratis A, Ruzicka T, Röcken M, Pfeffer K, Schmid RM, Rupec RA (2007) Crosstalk between keratinocytes and adaptive immune cells in an IκBα protein-mediated inflammatory disease of the skin. Immunity 27:296–307

    Article  CAS  PubMed  Google Scholar 

  • Saha A, Biswas A, Srivastav S, Mukherjee M, Das PK, Ukil A (2014) Prostaglandin E2 negatively regulates the production of inflammatory cytokines/chemokines and IL-17 in visceral leishmaniasis. J Immunol 193:2330–2339

    Article  CAS  PubMed  Google Scholar 

  • Schaerli P, Moser B (2005) Chemokines: control of primary and memory T-cell traffic. Immunol Res 31:57–74

    Article  CAS  PubMed  Google Scholar 

  • Schreiber E, Matthias P, Müller MM, Schaffner W (1989) Rapid detection of octamer binding proteins with ’mini-extracts’, prepared from a small number of cells. Nucleic Acids Res 17:6419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siomek A (2012) NF-κB signaling pathway and free radical impact. Acta Biochim Pol 59:323–331

    CAS  PubMed  Google Scholar 

  • Thomson AW, Turnquist HR, Raimondi G (2009) Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 9:324–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tokuhira N, Kitagishi Y, Suzuki M, Minami A, Nakanishi A, Ono Y, Kobayashi K, Matsuda S, Ogura Y (2015) PI3K/AKT/PTEN pathway as a target for Crohn’s disease therapy (review). Int J Mol Med 35:10–16

    CAS  PubMed  Google Scholar 

  • Vestergaard C, Johansen C, Otkjaer K, Deleuran M, Iversen L (2005) Tumor necrosis factor-alpha-induced CTACK/CCL27 (cutaneous T-cell-attracting chemokine) production in keratinocytes is controlled by nuclear factor κB. Cytokine 29:49–55

    Article  CAS  PubMed  Google Scholar 

  • Yamasaki C, Nishikawa K, Zeng XT, Katayama Y, Natori Y, Komatsu N, Oda T, Natori Y (2004) Induction of cytokines by toxins that have an identical RNA N-glycosidase activity: Shiga toxin, ricin, and modeccin. Biochim Biophys Acta 1671:44–50

    Article  CAS  PubMed  Google Scholar 

  • Young CN, Koepke JI, Terlecky LJ, Borkin MS, Boyd SL, Terlecky SR (2008) Reactive oxygen species in tumor necrosis factor-α-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. J Invest Dermatol 128:2606–2614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhong LM, Zong Y, Sun L, Guo JZ, Zhang W, He Y, Song R, Wang WM, Xiao CJ, Lu D (2012) Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PLoS One 7:e32195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This research was supported by the Chung-Ang University Research Scholarship Grants in 2016, Chung-Ang University, Seoul, South Korea.

Author information

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea

    Yoon Jeong Nam & Chung Soo Lee

Authors
  1. Yoon Jeong Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chung Soo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chung Soo Lee.

Ethics declarations

Keratinocytes were obtained and prepared from neonatal foreskin discarded after circumcision (Kim et al. 2005) in accordance with the Declaration of Helsinki Principles and the ethical guidelines of Chung-Ang University Hospital.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nam, Y.J., Lee, C.S. Brefeldin A reduces tumor necrosis factor-α-stimulated production of inflammatory mediators by suppressing the Akt, mTOR, and NF-κB pathways in human keratinocytes. Naunyn-Schmiedeberg's Arch Pharmacol 389, 951–960 (2016). https://doi.org/10.1007/s00210-016-1242-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-016-1242-6

Keywords

Search

Navigation