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Pneumolysin-mediated expression of β-defensin 2 is coordinated by p38 MAP kinase-MKP1 in human airway cells

Journal of Microbiology volume 51, pages 194–199 (2013)Cite this article

Abstract

Antimicrobial peptides act as important innate immune defense mediators against invading microbes such as Streptococcus pneumoniae. Among a number of antimicrobial peptides, β-defensin 2 (BD2) has strong antimicrobial activity against S. pneumoniae. However, little is known about the molecular signaling mechanisms leading to the BD2 expression. Here, we report that BD2 is strongly induced by S. pneumoniae in human airway cells including human middle-ear cells. Among diverse pneumococcal virulence factors, pneumolysin is required for inducing BD2 whose expression is under the control of p38 mitogen-activated protein kinase (MAPK). Pneumolysin also selectively regulates the expression of MAPK phosphatase 1 (MKP1), which inhibits the p38 signaling pathway, thereby leading to upregulation of BD2 to mount an effective defense against S. pneumoniae infection. These results provide novel insights into the molecular mechanisms underlying the coordinative regulation of BD2 expression via p38-MKP1 in the pathogenesis of airway infectious diseases.

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References

  • Avery, O.T., MacLeod, C.M., and McCarty, M. 1979. Studies on the chemical nature of the substance inducing transformation of pneumococcal types. Inductions of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J. Exp. Med. 149, 297–326.

    PubMed  Article  CAS  Google Scholar 

  • Berry, A.M., Yother, J., Briles, D.E., Hansman, D., and Paton, J.C. 1989. Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect. Immun. 57, 2037–2042.

    PubMed  CAS  Google Scholar 

  • Black, S., Shinefield, H., Fireman, B., Lewis, E., Ray, P., Hansen, J.R., Elvin, L., Ensor, K.M., Hackell, J., Siber, G., and et al. 2000. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr. Infect. Dis. J. 19, 187–195.

    PubMed  Article  CAS  Google Scholar 

  • Briles, D.E., Crain, M.J., Gray, B.M., Forman, C., and Yother, J. 1992. Strong association between capsular type and virulence for mice among human isolates of Streptococcus pneumoniae. Infect. Immun. 60, 111–116.

    PubMed  CAS  Google Scholar 

  • Canvin, J.R., Marvin, A.P., Sivakumaran, M., Paton, J.C., Boulnois, G.J., Andrew, P.W., and Mitchell, T.J. 1995. The role of pneumolysin and autolysin in the pathology of pneumonia and septicemia in mice infected with a type 2 pneumococcus. J. Infect. Dis. 172, 119–123.

    PubMed  Article  CAS  Google Scholar 

  • Chun, Y.M., Moon, S.K., Lee, H.Y., Webster, P., Brackmann, D.E., Rhim, J.S., and Lim, D.J. 2002. Immortalization of normal adult human middle ear epithelial cells using a retrovirus containing the E6/E7 genes of human papillomavirus type 16. Ann. Otol. Rhinol. Laryngol. 111, 507–517.

    PubMed  Google Scholar 

  • De Smet, K. and Contreras, R. 2005. Human antimicrobial peptides: Defensins, cathelicidins and histatins. Biotechnol. Lett. 27, 1337–1347.

    PubMed  Article  Google Scholar 

  • Duits, L.A., Rademaker, M., Ravensbergen, B., van Sterkenburg, M.A., van Strijen, E., Hiemstra, P.S., and Nibbering, P.H. 2001. Inhibition of hBD-3, but not hBD-1 and hBD-2, mRNA expression by corticosteroids. Biochem. Biophys. Res. Commun. 280, 522–525.

    PubMed  Article  CAS  Google Scholar 

  • Franklin, C.C. and Kraft, A.S. 1997. Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells. J. Biol. Chem. 272, 16917–16923.

    PubMed  Article  CAS  Google Scholar 

  • Ha, U., Lim, J.H., Jono, H., Koga, T., Srivastava, A., Malley, R., Pages, G., Pouyssegur, J., and Li, J.D. 2007. A novel role for IKB kinase (IKK) α and IKKβ in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae. J. Immunol. 178, 1736–1747.

    PubMed  CAS  Google Scholar 

  • Ha, U.H., Lim, J.H., Kim, H.J., Wu, W., Jin, S., Xu, H., and Li, J.D. 2008. MKP1 regulates the induction of MUC5AC mucin by Streptococcus pneumoniae pneumolysin by inhibiting the PAK4-JNK signaling pathway. J. Biol. Chem. 283, 30624–30631.

    PubMed  Article  CAS  Google Scholar 

  • Harder, J., Meyer-Hoffert, U., Teran, L.M., Schwichtenberg, L., Bartels, J., Maune, S., and Schroder, J.M. 2000. Mucoid Pseudomonas aeruginosa, TNF-α, and IL-1β, but not IL-6, induce human β-defensin-2 in respiratory epithelia. Am. J. Respir. Cell. Mol. Biol. 22, 714–721.

    PubMed  Article  CAS  Google Scholar 

  • Hiemstra, P.S. 2007. The role of epithelial β-defensins and cathelicidins in host defense of the lung. Exp. Lung Res. 33, 537–542.

    PubMed  Article  CAS  Google Scholar 

  • Hiratsuka, T., Mukae, H., Iiboshi, H., Ashitani, J., Nabeshima, K., Minematsu, T., Chino, N., Ihi, T., Kohno, S., and Nakazato, M. 2003. Increased concentrations of human β-defensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Thorax 58, 425–430.

    PubMed  Article  CAS  Google Scholar 

  • Hobbie, S., Chen, L.M., Davis, R.J., and Galan, J.E. 1997. Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J. Immunol. 159, 5550–5559.

    PubMed  CAS  Google Scholar 

  • Huttner, K.M. and Bevins, C.L. 1999. Antimicrobial peptides as mediators of epithelial host defense. Pediatr. Res. 45, 785–794.

    PubMed  Article  CAS  Google Scholar 

  • Ishimoto, H., Mukae, H., Date, Y., Shimbara, T., Mondal, M.S., Ashitani, J., Hiratsuka, T., Kubo, S., Kohno, S., and Nakazato, M. 2006. Identification of hBD-3 in respiratory tract and serum: The increase in pneumonia. Eur. Respir. J. 27, 253–260.

    PubMed  Article  CAS  Google Scholar 

  • Jang, B.C., Lim, K.J., Paik, J.H., Kwon, Y.K., Shin, S.W., Kim, S.C., Jung, T.Y., Kwon, T.K., Cho, J.W., Baek, W.K., and et al. 2004. Up-regulation of human β-defensin 2 by interleukin-1β in A549 cells: Involvement of PI3K, PKC, p38 MAPK, JNK, and NF-kappaB. Biochem. Biophys. Res. Commun. 320, 1026–1033.

    PubMed  Article  CAS  Google Scholar 

  • Jang, B.C., Lim, K.J., Suh, M.H., Park, J.G., and Suh, S.I. 2007. Dexamethasone suppresses interleukin-1β-induced human β-defensin 2 mRNA expression: involvement of p38 MAPK, JNK, MKP-1, and NF-KB transcriptional factor in A549 cells. FEMS Immunol. Med. Microbiol. 51, 171–184.

    PubMed  Article  CAS  Google Scholar 

  • Lee, H.Y., Andalibi, A., Webster, P., Moon, S.K., Teufert, K., Kang, S.H., Li, J.D., Nagura, M., Ganz, T., and Lim, D.J. 2004. Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae. BMC Infect. Dis. 4, 12.

    PubMed  Article  Google Scholar 

  • Lee, H.Y., Takeshita, T., Shimada, J., Akopyan, A., Woo, J.I., Pan, H., Moon, S.K., Andalibi, A., Park, R.K., Kang, S.H., and et al. 2008. Induction of β defensin 2 by NTHi requires TLR2 mediated MyD88 and IRAK-TRAF6-p38MAPK signaling pathway in human middle ear epithelial cells. BMC Infect. Dis. 8, 87.

    PubMed  Article  Google Scholar 

  • Li, Q., Estepa, G., Memet, S., Israel, A., and Verma, I.M. 2000. Complete lack of NF-KB activity in IKK1 and IKK2 double-deficient mice: Additional defect in neurulation. Genes Dev. 14, 1729–1733.

    PubMed  CAS  Google Scholar 

  • Li, Q., Lu, Q., Hwang, J.Y., Buscher, D., Lee, K.F., Izpisua-Belmonte, J.C., and Verma, I.M. 1999. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13, 1322–1328.

    PubMed  Article  CAS  Google Scholar 

  • MacRedmond, R., Greene, C., Taggart, C.C., McElvaney, N., and O’Neill, S. 2005. Respiratory epithelial cells require Toll-like receptor 4 for induction of human β-defensin 2 by lipopolysaccharide. Respir. Res. 6, 116.

    PubMed  Article  Google Scholar 

  • Mikami, F., Gu, H., Jono, H., Andalibi, A., Kai, H., and Li, J.D. 2005. Epidermal growth factor receptor acts as a negative regulator for bacterium nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via an Src-dependent p38 mitogen-activated protein kinase signaling pathway. J. Biol. Chem. 280, 36185–36194. Epub 32005 Aug 36122.

    PubMed  Article  CAS  Google Scholar 

  • Mitchell, T.J. 2006. Streptococcus pneumoniae: Infection, inflammation and disease. Adv. Exp. Med. Biol. 582, 111–124.

    PubMed  Article  Google Scholar 

  • Obaro, S.K. 2002. The new pneumococcal vaccine. Clin. Microbiol. Infect. 8, 623–633.

    PubMed  Article  CAS  Google Scholar 

  • Scharf, S., Zahlten, J., Szymanski, K., Hippenstiel, S., Suttorp, N., and N’Guessan, P.D. 2012. Streptococcus pneumoniae induces human β-defensin-2 and -3 in human lung epithelium. Exp. Lung Res. 38, 100–110.

    PubMed  Article  CAS  Google Scholar 

  • Schroder, J.M. 1999. Epithelial peptide antibiotics. Biochem. Pharmacol. 57, 121–134.

    PubMed  Article  CAS  Google Scholar 

  • Terai, K., Sano, Y., Kawasaki, S., Endo, K., Adachi, W., Hiratsuka, T., Ihiboshi, H., Nakazato, M., and Kinoshita, S. 2004. Effects of dexamethasone and cyclosporin A on human β-defensin in corneal epithelial cells. Exp. Eye Res. 79, 175–180.

    PubMed  Article  CAS  Google Scholar 

  • Welte, T. and Kohnlein, T. 2009. Global and local epidemiology of community-acquired pneumonia: The experience of the CAPNETZ Network. Semin. Respir. Crit. Care Med. 30, 127–135.

    PubMed  Article  Google Scholar 

  • Wheeler, J., Freeman, R., Steward, M., Henderson, K., Lee, M.J., Piggott, N.H., Eltringham, G.J., and Galloway, A. 1999. Detection of pneumolysin in sputum. J. Med. Microbiol. 48, 863–866.

    PubMed  Article  CAS  Google Scholar 

  • Yang, F., Tang, E., Guan, K., and Wang, C.Y. 2003. IKKβ plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide. J. Immunol. 170, 5630–5635.

    PubMed  CAS  Google Scholar 

  • Yoo, I.H., Shin, H.S., Kim, Y.J., Kim, H.B., Jin, S., and Ha, U.H. 2010. Role of pneumococcal pneumolysin in the induction of an inflammatory response in human epithelial cells. FEMS Immunol. Med. Microbiol. 60, 28–35.

    PubMed  Article  CAS  Google Scholar 

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Affiliations

  1. Department of Biotechnology and Bioinformatics, Korea University, Sejong, 339-700, Republic of Korea

    Yong-Jae Kim, Hee-Sung Shin, Jung-Hoon Lee, Hyong-Bai Kim & Un-Hwan Ha

  2. College of Pharmacy, Korea University, Sejong, 339-700, Republic of Korea

    Yong Woo Jung

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  1. Yong-Jae Kim
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  2. Hee-Sung Shin
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  3. Jung-Hoon Lee
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  4. Yong Woo Jung
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  5. Hyong-Bai Kim
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  6. Un-Hwan Ha
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Correspondence to Hyong-Bai Kim or Un-Hwan Ha.

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Kim, YJ., Shin, HS., Lee, JH. et al. Pneumolysin-mediated expression of β-defensin 2 is coordinated by p38 MAP kinase-MKP1 in human airway cells. J Microbiol. 51, 194–199 (2013). https://doi.org/10.1007/s12275-013-2579-x

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  • DOI: https://doi.org/10.1007/s12275-013-2579-x

Keywords

  • hBD2
  • MKP1
  • p38
  • pneumolysin