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Irsogladine Maleate Regulates Gap Junctional Intercellular Communication-Dependent Epithelial Barrier in Human Nasal Epithelial Cells

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Abstract

The airway epithelium of the human nasal mucosa acts as the first physical barrier that protects against inhaled substances and pathogens. Irsogladine maleate (IM) is an enhancer of gastric mucosal protective factors via upregulation of gap junctional intercellular communication (GJIC). GJIC is thought to participate in the formation of functional tight junctions. However, the effects of IM on GJIC and the epithelial barrier in human nasal epithelial cells (HNECs) remain unknown. To investigate the effects of IM on GJIC and the tight junctional barrier in HNECs, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were treated with IM and the GJIC inhibitors oleamide and 18β-GA. Some cells were pretreated with IM before treatment with TLR3 ligand poly(I:C) to examine whether IM prevented the changes via TLR3-mediated signal pathways. In hTERT-HNECs, GJIC blockers reduced the expression of tight junction molecules claudin-1, -4, -7, occludin, tricellulin, and JAM-A. IM induced GJIC activity and enhanced the expression of claudin-1, -4, and JAM-A at the protein and mRNA levels with an increase of barrier function. GJIC blockers prevented the increase of the tight junction proteins induced by IM. Furthermore, IM prevented the reduction of JAM-A but not induction of IL-8 and TNF-α induced by poly(I:C). In conclusion, IM can maintain the GJIC-dependent tight junctional barrier via regulation of GJIC in upper airway nasal epithelium. Therefore, it is possible that IM may be useful as a nasal spray to prevent the disruption of the epithelial barrier by viral infections and exposure to allergens in human nasal mucosa.

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References

  • El-Fouly MH, Trosko JE, Chang CC (1987) Scrape-loading and dye transfer. A rapid and simple technique to study gap junctional intercellular communication. Exp Cell Res 168:422–430

    Article  CAS  PubMed  Google Scholar 

  • Fujita T, Yumoto H, Shiba H, Ouhara K, Miyagawa T, Nagahara T, Matsuda S, Kawaguchi H, Matsuo T, Murakami S, Kurihara H (2012) Irsogladine maleate regulates epithelial barrier function in tumor necrosis factor-α-stimulated human gingival epithelial cells. J Periodontal Res 47:55–61

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Mariscal L, Tapia R, Chamorro D (2008) Crosstalk of tight junction components with signaling pathways. Biochim Biophys Acta 1778:729–756

    Article  CAS  PubMed  Google Scholar 

  • Hiraishi H, Haruma K, Miwa H, Goto H (2010) Clinical trial, irsogladine maleate, a mucosal protective drug, accelerates gastric ulcer healing after treatment for eradication of Helicobacter pylori infection-the results of a multicentre, double-blind, randomized clinical trial (IMPACT study). Aliment Pharmacol Ther 31:824–833

    CAS  PubMed  Google Scholar 

  • Holgate ST (2007) Epithelium dysfunction in asthma. J Allergy Clin Immunol 120:1233–1244

    Article  CAS  PubMed  Google Scholar 

  • Ito T, Ogoshi K, Nakano I, Ueda F, Sakai H, Kinjo M, Nawata H (1997) Effect of Irsogladine on gap junctions in cerulein-induced acute pancreatitis in rats. Pancreas 15:297–303

    Article  CAS  PubMed  Google Scholar 

  • Kamekura R, Kojima T, Koizumi J, Ogasawara N, Kurose M, Go M, Harimaya A, Murata M, Tanaka S, Chiba H, Himi T, Sawada N (2009) Thymic stromal lymphopoietin enhances tight-junction barrier function of human nasal epithelial cells. Cell Tissue Res 338:283–293

    Article  CAS  PubMed  Google Scholar 

  • Koizumi J, Kojima T, Kamekura R, Kurose M, Harimaya A, Murata M, Osanai M, Chiba H, Himi T, Sawada N (2007) Changes of gap and tight junctions during differentiation of human nasal epithelial cells using primary human nasal epithelial cells and primary human nasal fibroblast cells in a noncontact coculture system. J Membr Biol 218:1–7

    Article  CAS  PubMed  Google Scholar 

  • Koizumi J, Kojima T, Ogasawara N, Kamekura R, Kurose M, Go M, Harimaya A, Murata M, Osanai M, Chiba H, Himi T, Sawada N (2008) Protein kinase C enhances tight junction barrier function of human nasal epithelial cells in primary culture by transcriptional regulation. Mol Pharmacol 74:432–442

    Article  CAS  PubMed  Google Scholar 

  • Kojima T, Spray D, Kokai Y, Chiba H, Mochizuki Y, Sawada N (2002) Cx32 formation and/or Cx32-mediated intercellular communication induces expression and function of tight junctions in hepatocytic cell line. Exp Cell Res 276:40–51

    Article  CAS  PubMed  Google Scholar 

  • Kojima T, Murata M, Go M, Spray DC, Sawada N (2007) Connexins induce and maintain tight junctions in epithelial cells. J Membr Biol 217:13–19

    Article  CAS  PubMed  Google Scholar 

  • Kojima T, Murata M, Yamamoto T, Lan M, Imamura M, Son S, Takano K, Yamaguchi H, Ito T, Tanaka S, Chiba H, Hirata K, Sawada N (2009) Tight junction proteins and signal transduction pathways in hepatocytes. Histol Histopathol 24:1463–1472

    CAS  PubMed  Google Scholar 

  • Kojima T, Go M, Takano K, Kurose M, Ohkuni T, Koizumi J, Kamekura R, Ogasawara N, Masaki T, Fuchimoto J, Obata K, Hirakawa S, Nomura K, Keira T, Miyata R, Fujii N, Tsutsumi H, Himi T, Sawada N (2013) Regulation of tight junction in upper airway epithelium. Biomed Res Int. doi:10.1155/2013/947072

    Google Scholar 

  • Kumar NM, Gilula NB (1996) The gap junction communication channel. Cell 84:381–388

    Article  CAS  PubMed  Google Scholar 

  • Kurose M, Kojima T, Koizumi J, Kamekura R, Ninomiya T, Murata M, Ichimiya S, Osanai M, Chiba H, Himi T, Sawada N (2007) Induction of claudins in passaged hTERT-transfected human nasal epithelial cells with an extended life span. Cell Tissue Res 330:63–74

    Article  CAS  PubMed  Google Scholar 

  • Loewenstein WR (1979) Junctional intercellular communication and the control of growth. Biochim Biophys Acta 560:1–65

    CAS  PubMed  Google Scholar 

  • Morita H, Katsuno T, Hoshimoto A, Hirano N, Saito Y, Suzuki Y (2004) Connexin 26-mediated gap junctional intercellular communication suppresses paracellular permeability of human intestinal epithelial cell monolayers. Exp Cell Res 298:1–8

    Article  CAS  PubMed  Google Scholar 

  • Ogasawara N, Kojima T, Go M, Ohkuni T, Koizumi J, Kamekura R, Masaki T, Murata M, Tanaka S, Fuchimoto J, Himi T, Sawada N (2010) PPARgamma agonists upregulate the barrier function of tight junctions via a PKC pathway in human nasal epithelial cells. Pharmacol Res 61:489–498

    Article  CAS  PubMed  Google Scholar 

  • Ohkuni T, Kojima T, Ogasawara N, Masaki T, Ninomiya T, Kikuchi S, Go M, Takano K, Himi T, Sawada N (2009) Expression and localization of tricellulin in human nasal epithelial cells in vivo and in vitro. Med Mol Morphol 42:204–211

    Article  CAS  PubMed  Google Scholar 

  • Ohkuni T, Kojima T, Ogasawara N, Masaki T, Fuchimoto J, Kamekura R, Koizumi J, Ichimiya S, Murata M, Tanaka S, Himi T, Sawada N (2011) Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-α via distinct NF-κB pathways in human nasal epithelial cells. Toxicol Appl Pharmacol 250:29–38

    Article  CAS  PubMed  Google Scholar 

  • Saez JC, Spray DC, Nairn AC, Hertzberg E, Greengard P, Bennett MV (1986) cAMP increases junctional conductance and stimulates phosphorylation of the 27-kDa principal gap junction polypeptide. Proc Natl Acad Sci USA 83:2473–2477

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Savitri IJ, Ouhara K, Fujita T, Kajiya M, Miyagawa T, Kittaka M, Yamakawa M, Shiba H, Kurihara H (2014) Irsogladine maleate inhibits Porphyromonas gingivalis-mediated expression of toll-like receptor 2 and interleukin-8 in human gingival epithelial cells. J Periodontal Res. doi:10.1111/jre.12231

    PubMed  Google Scholar 

  • Sawada N, Murata M, Kikuchi K, Osanai M, Tobioka H, Kojima T, Chiba H (2003) Tight junctions and human diseases. Med Electron Microsc 36:147–156

    Article  PubMed  Google Scholar 

  • Schneeberger EE, Lynch RD (2004) The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 286:1213–1228

    Article  Google Scholar 

  • Takano K, Kojima T, Go M, Murata M, Ichimiya S, Himi T, Sawada N (2005) HLA-DR- and CD11c-positive dendritic cells penetrate beyond well-developed epithelial tight junctions in human nasal mucosa of allergic rhinitis. J Histochem Cytochem 53:611–619

    Article  CAS  PubMed  Google Scholar 

  • Trosko JE, Ruch RJ (1998) Cell–cell communication in carcinogenesis. Front Biosci 15:208–236

    Google Scholar 

  • Tsukita S, Furuse M, Itoh M (2001) Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2:285–293

    Article  CAS  PubMed  Google Scholar 

  • Uchida Y, Shiba H, Komatsuzawa H, Hirono C, Ashikaga A, Fujita T, Kawaguchi H, Sugai M, Shiba Y, Kurihara H (2005) Irsogladine maleate influences the response of gap junctional intercellular communication and IL-8 of human gingival epithelial cells following periodontopathogenic bacterial challenge. Biochem Biophys Res Commun 333:502–507

    Article  CAS  PubMed  Google Scholar 

  • Ueda F, Kyoi T, Mimura K, Kimura K, Yamamoto M (1991) Intercellular communication in cultured rabbit gastric epithelial cells. Jpn J Pharmacol 57:321–328

    Article  CAS  PubMed  Google Scholar 

  • Yamasaki H, Naus CC (1996) Role of connexin genes in growth control. Carcinogenesis 17:1199–1213

    Article  CAS  PubMed  Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan

    Ryo Miyata, Kazuaki Nomura, Takuya Kakuki, Ken-ichi Takano & Tetsuo Himi

  2. Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan

    Norimasa Sawada

  3. Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S1., W17., Sapporo, 060-8556, Japan

    Ryo Miyata, Takuya Kakuki, Takayuki Kohno, Takumi Konno & Takashi Kojima

Authors
  1. Ryo Miyata
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  2. Kazuaki Nomura
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  3. Takuya Kakuki
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  4. Ken-ichi Takano
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  5. Takayuki Kohno
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  6. Takumi Konno
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  7. Norimasa Sawada
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  8. Tetsuo Himi
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  9. Takashi Kojima
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Correspondence to Takashi Kojima.

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Miyata, R., Nomura, K., Kakuki, T. et al. Irsogladine Maleate Regulates Gap Junctional Intercellular Communication-Dependent Epithelial Barrier in Human Nasal Epithelial Cells. J Membrane Biol 248, 327–336 (2015). https://doi.org/10.1007/s00232-015-9774-0

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  • DOI: https://doi.org/10.1007/s00232-015-9774-0

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