Syntheses of Prostaglandin E2 and E-Cadherin and Gene Expression of β-defensin-2 by Human Gingival Epithelial Cells in Response to Actinobacillus actinomycetemcomitans


The interaction between epithelial cells and microorganisms is the most important step in bacterial infections. Actinobacillus actinomycetemcomitans was suggested to play a significant role in the initiation of periodontitis because of its bacteriological characteristics. Prostaglandins (PG) mediate the inflammatory response. Human β-defensin-2 (hBD-2) is an antimicrobial peptide and contributes to innate immunity. E-cadherin is responsible for an epithelial intercellular junction. In this study, we investigated the syntheses of PGE2 and E-cadherin and the expression of hBD-2 in human gingival epithelial cells (HGEC) following exposure to A. actinomycetemcomitans. The levels of PGE2 and cyclooxygenase-2, which are responsible for an increase in PGE2, were increased depending on bacteria exposure time. hBD-2 mRNA was induced by A. actinomycetemcomitans, while HGEC exposed to A. actinomycetemcomitans showed a decrease in E-cadherin levels. Etodolac, a selective cyclooxygenase-2 inhibitor reinforced the increase in hBD-2 mRNA levels by A. actinomycetemcomitans. Furthermore, the etodolac suppressed the decrease in E-cadherin levels. Thus, endogenous PGE2 is involved in the hBD-2 and E-cadherin responses of HGEC to A. actinomycetemcomitans. These findings suggest that the inflammatory and antimicrobial response of gingival epithelial cells to A. actinomycetemcomitans is involved in the initiation of periodontal inflammation. A. actinomycetemcomitans may destroy the mechanical epithelial barrier by destroying E-cadherin.

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  1. 1.

    Fleiszig, S. M., D. J. Evans, N. Do, V. Vallas, S. Shin and K. E. Mostov. 1997. Epithelial cell polarity affects susceptibility to Pseudomonas aeruginosa invasion and cytotoxicity. Infect. Immun. 65:2861–2867.

    Google Scholar 

  2. 2.

    Katz, J., V. Sambandam, J. H. Wu, S. M. Michalek, and D. F. Balkovetz. 2000. Characterization of Porphyromonas gingivalis-induced degradation of epithelial cell junctional complexes. Infect. Immun. 68:1441–1449.

    Google Scholar 

  3. 3.

    Harder, J., J. Bartels, E. Christophers, and J. M. Schroder. 1997. A peptide antibiotic from human skin. Nature 387:861.

    Google Scholar 

  4. 4.

    O'Neil, D. A., S. P. Cole, E. Martin-Porter, M. P. Housley, L. Liu, T. Ganz and M. F. Kagnoff. 2000. Regulation of human β-defensins by gastric epithelial cells in response to infection with Helicobacter pylori or stimulation with interleukin-1. Infect. Immun. 68:5412–5415.

    Google Scholar 

  5. 5.

    Hamanaka, Y., M. Nakashima, A. Wada, M. Ito, H. Kurazono, H. Hojo, Y. Nakahara, S. Kohno, T. Hirayama, and I. Sekine. 2001. Expression of human β-defensin 2 (hBD-2) in Helicobacter pylori induced gastritis: Antibacterial effect of hBD-2 against Helicobacter pylori. Gut 49:481–487.

    Google Scholar 

  6. 6.

    Krisanaprakornkit, S., J. R. Kimball, A. Weinberg, R. P. Darveau, B. W. Bainbridge, and B. A. Dale. 2000. Inducible expression of human β-defensin 2 by Fusobacterium nucleatum in oral epithelial cells: Multiple signaling pathways and role of commensal bacteria in innate immunity and the epithelial barrier. Infect. Immun. 68:2907–2915.

    Google Scholar 

  7. 7.

    O'Neil, D. A., E. M. Porter, D. Elewaut, G. M. Anderson, L. Eckmann, T. Ganz, and M. F. Kagnoff. 1999. Expression and regulation of the human β-defensins hBD-1 and hBD-2 in intestinal epithelium. J. Immunol. 163(12):6718–6724.

    Google Scholar 

  8. 8.

    Schröder, J. M. and J. Harder. 1999. Human beta-defensin-2. Int. J. Biochem. Cell Biol. 31:645–651.

    Google Scholar 

  9. 9.

    Uchida, Y., H. Shiba, H. Komatsuzawa, T. Takemoto, M. Sakata, T. Fujita, H. Kawaguchi, M. Sugai, and H. Kurihara. 2001. Expression of IL-1β and IL-8 by human gingival epithelial cells in response to Actinobacillus actinomycetemcomitans. Cytokine 14:152–161.

    Google Scholar 

  10. 10.

    Yumoto, H., H. Nakae, M. Yamada, K. Fujinaka, C. Shinohara, S. Ebisu and T. Matsuo. 2001. Soluble products from Eikenella corrodens stimulate oral epithelial cells to induce inflammatory mediators. Oral Microbiol. Immunol. 16:296–305.

    Google Scholar 

  11. 11.

    Laurent, F., M. F. Kagnoff, T. C. Savidge, M. Naciri, and L. Eckmann. 1998. Human intestinal epithelial cells respond to Cryptosporidium parvum infection with increased prostaglandin H synthase 2 expression and prostaglandin E2 and F production. Infect. Immun. 66:1787–1790.

    Google Scholar 

  12. 12.

    Wang, B., N. Ruiz, A. Pentland, and M. Caparon. 1997. Keratinocyte proinflammatory responses to adherent and nonadherent group A streptococci. Infect. Immun. 65:2119–2126.

    Google Scholar 

  13. 13.

    Lin, C. H., I. H. Kuan, H. M. Lee, W. S. Lee, J. R. Sheu, Y. S. Ho, C. H. Wang, and H. P. Kuo. 2001. Induction of cyclooxygenase-2 protein by lipoteichoic acid from Staphylococcus aureus in human pulmonary epithelial cells: Involvement of a nuclear factor-κ-dependent pathway. Br. J. Pharmacol. 134:543–552.

    Google Scholar 

  14. 14.

    Mendieta, C. F., C. M. Reeve, and J. C. Romero. 1985. Biosynthesis of prostaglandins in gingiva of patients with chronic periodontitis. J. Periodontol. 56:44–47.

    Google Scholar 

  15. 15.

    Tsai, C. C., Y. C. Hong, C. C. Chen, and Y. M. Wu. 1998. Measurement of prostaglandin E2 and leukotriene B4 in the gingival crevicular fluid. J. Dent. 26:97–103.

    Google Scholar 

  16. 16.

    Yucel-Lindberg, T., H. Ahola, S. Nilsson, J. Carlstedt-Duke, and T. Modeer. 1995. Interleukin-1β induces expression of cyclooxygenase-2 mRNA in human gingival fibroblasts. Inflammation 19:549–560.

    Google Scholar 

  17. 17.

    Scott, M. G. and R. E. Hancock. 2000. Cationic antimicrobial peptides and their multifunctional role in the immune system. Crit. Rev. Immunol. 20:407–431.

    Google Scholar 

  18. 18.

    Wheelock, M. J. and P. J. Jensen. 1992. Regulation of keratinocyte intercellular junction organization and epidermal morphogenesis by E-cadherin. J. Cell Biol. 117:415–425.

    Google Scholar 

  19. 19.

    Rodriguez-Boulan, E. and W. J. Nelson. 1989. Morphogenesis of the polarized epithelial cell phenotype. Science 245:718–725.

    Google Scholar 

  20. 20.

    Ye P., C. C. Chapple, R. K. Kumar, N. Hunter. 2000. Expression patterns of E-cadherin, involucrin, and connexin gap junction proteins in the lining epithelia of inflamed gingiva. J. Pathol. 192:58–66.

    Google Scholar 

  21. 21.

    Obiso, R. J. Jr, A. O. Azghani, and T. D. Wilkins. 1997. The Bacteroides fragilis toxin fragilysin disrupts the paracellular barrier of epithelial cells. Infect. Immun. 65:1431–1439.

    Google Scholar 

  22. 22.

    Wu, S., K. C. Lim, J. Huang, R. F. Saidi, and C. L. Sears. 1998. Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc. Natl. Acad. Sci. U.S.A. 95:14979–14984.

    Google Scholar 

  23. 23.

    Wilson, M. and B. Henderson. 1995. Virulence factors of Actinobacillus actinomycetemcomitans relevant to the pathogenesis of inflammatory periodontal diseases. FEMS Microbiol. Rev. 17:365–379.

    Google Scholar 

  24. 24.

    Meyer, D. H. and P. M. Fives-Taylor. 1997. The role of Actinobacillus actinomycetemcomitans in the pathogenesis of periodontal disease. Trends Microbiol. 5:224–228.

    Google Scholar 

  25. 25.

    Fives-Taylor, P. M., D. H. Meyer, K. P. Mintz, C. Brissette. 1999. Virulence factors of Actinobacillus actinomycetemcomitans. Periodontol. 2000. 20:136–167.

    Google Scholar 

  26. 26.

    Huang, G. T., S. K. Haake, J. W. Kim, and N. H. Park. 1998. Differential expression of interleukin-8 and intercellular adhesion molecule-1 by human gingival epithelial cells in response to Actinobacillus actinomycetemcomitans or Porphyromonas gingivalis infection. Oral Microbiol. Immunol. 13:301–309.

    Google Scholar 

  27. 27.

    Sato, J. D., T. Kawamoto, and T. Okamoto. 1987. Cholesterol requirement of P3-X63-Ag8 and X63-Ag8.653 mouse myeloma cells for growth in vitro. J. Exp. Med. 165:1761–1766.

    Google Scholar 

  28. 28.

    Myoken, Y., Y. Myoken, T. Okamoto, J. D. Sato, and K. Takada. 1995. Effect of fibroblast growth factor-1 on the three-dimensional growth and morphogenesis of human salivary gland epithelial cells embedded in collagen gels. In Vitro Cell. Dev. Biol. Anim. 31:84–86.

    Google Scholar 

  29. 29.

    Yuspa, S. H. and C. C. Harris. 1974. Altered differentiation of mouse epidermal cells treated with retinyl acetate in vitro. Exp. Cell Res. 86:95–105.

    Google Scholar 

  30. 30.

    Krisanaprakornkit, S., A. Weinberg, C. N. Perez, and B. A. Dale. 1998. Expression of the peptide antibiotic human β-defensin 1 in cultured gingival epithelial cells and gingival tissue. Infect. Immun. 66:4222–4228.

    Google Scholar 

  31. 31.

    Kawamoto, T., H. Pan, W. Yan, H. Ishida, E. Usui, R. Oda, K. Nakamasu, M. Noshiro, Y. Kawashima-Ohya, M. Fujii, H. Shintani, Y. Okada, and Y. Kato. 1998. Expression of membrane-bound transferrin-like protein p97 on the cell surface of chondrocytes. Eur. J. Biochem. 256:503–509.

    Google Scholar 

  32. 32.

    Thomas, P. S. 1980. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc. Natl. Acad. Sci. U.S.A. 77:5201–5205.

    Google Scholar 

  33. 33.

    Sakata, M., H. Shiba, H. Komatsuzawa, T. Fujita, Y. Uchida, H. Yoshino, T. Ogawa, H. Kawaguchi, and H. Kurihara. 2002. Osteoprotegegerin levels increased by interleukin-1β in human periodontal ligament cells are suppressed throught prostaglandin E2 synthesized de novo. Cytokine 18:133–139.

    Google Scholar 

  34. 34.

    DeWitt, D. L. 1991. Prostaglandin endoperoxide synthase: Regulation of enzyme expression. Biochim. Biophys. Acta 1083:121–134.

    Google Scholar 

  35. 35.

    Pentland, A. P. and Needleman, P. 1986. Modulation of keratinocyte proliferation in vitro by endogenous prostaglandin synthesis. J. Clin. Invest. 77:246–251.

    Google Scholar 

  36. 36.

    Pentland, A. P., J. George, C. Moran, and P. Needleman. 1987. Cellular confluence determines injury-induced prostaglandin E2 synthesis by human keratinocyte cultures. Biochim. Biophys. Acta 919:71–78.

    Google Scholar 

  37. 37.

    Rys-Sikora, K. E., R. L. Konger, J. W. Schoggins, R. Malaviya, and A. P. Pentland. 2000. Coordinate expression of secretory phospholipase A2 and cyclooxygenase-2 in activated human keratinocytes. Am. J. Physiol. Cell Physiol. 278:C822-C833.

    Google Scholar 

  38. 38.

    Knudsen, P. J., C. A. Dinarello, and T. B. Strom. 1986. Prostaglandins posttranscriptionally inhibit monocyte expression of interleukin 1 activity by increasing intracellular cyclic adenosine monophosphate. J. Immunol. 137:3189–3194.

    Google Scholar 

  39. 39.

    Baer, P. N. 1971. The case for periodontosis as a clinical entity. J. Periodontol. 42:516–520.

    Google Scholar 

  40. 40.

    Ulevitch, R. J. and P. S. Tobias. 1995. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13:437–457.

    Google Scholar 

  41. 41.

    Smith, J. J., S. M. Travis, E. P. Greenberg, and M. J. Welsh. 1996. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell. 85(2):229–236.

    Google Scholar 

  42. 42.

    Frye, M., J. Bargon, and R. Gropp. 2001. Expression of human beta-defensin-1 promotes differentiation of keratinocytes. J. Mol. Med. 79:275–282.

    Google Scholar 

  43. 43.

    Noda, M., Y. Tatsumi, M. Tomizawa, T. Takama, S. Mitsufuji, H. Sugihara, K. Kashima, and T. Hattori. 2002. Effects of etodolac, a selective cyclooxygenase-2 inhibitor, on the expression of E-cadherin-catenin complexes in gastrointestinal cell lines. J. Gastroenterol. 37:896–904.

    Google Scholar 

  44. 44.

    Canny, G., O. Levy, G. T. Furuta, S. Narravula-Alipati, R. B. Sisson, C. N. Serhan, and S. P. Colgan. 2002. Lipid mediator-induced expression of bactericidal/permeability-increasing protein (BPI) in human mucosal epithelia. Proc. Natl. Acad. Sci. U.S.A. 99:3902–3907.

    Google Scholar 

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Correspondence to Hideki Shiba.

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Noguchi, T., Shiba, H., Komatsuzawa, H. et al. Syntheses of Prostaglandin E2 and E-Cadherin and Gene Expression of β-defensin-2 by Human Gingival Epithelial Cells in Response to Actinobacillus actinomycetemcomitans . Inflammation 27, 341–349 (2003).

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  • Actinobacillus actinomycetemcomitans
  • gingival epithelial cells
  • prostaglandin E2
  • E-cadherin
  • β-defensin-2