Skip to main content
SpringerLink
Log in

MKP1 regulates the induction of MCP1 by Streptococcus pneumoniae pneumolysin in human epithelial cells

  • Published:
Molecules and Cells

Abstract

Epithelial cells act as the first line of host defense against microbes by producing a range of different molecules for clearance. Chemokines facilitate the clearance of invaders through the recruitment of leukocytes. Thus, upregulation of chemokine expression represents an important innate host defense response against invading microbes such as Streptococcus pneumoniae. In this study, we report that the expression of Monocyte Chemotactic Protein 1 (MCP1) was highly induced in response to S. pneumoniae in vitro and in vivo. Among numerous virulence factors, pneumococcal pneumolysin was found to be the major factor responsible for this induction. Furthermore, MCP1 induction was mediated by the p38 mitogen-activated protein kinase (MAPK) whose activation was controlled by MAPK phosphatase 1 (MKP1). Therefore, this study reveals novel roles of pneumolysin in mediating MKP1 expression for the regulation of MCP1 expression in human epithelial cells.

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

Similar content being viewed by others

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.

    Article  CAS  PubMed  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.

    CAS  PubMed  Google Scholar 

  • Black, S., Shinefield, H., Fireman, B., Lewis, E., Ray, P., Hansen, J.R., Elvin, L., Ensor, K.M., Hackell, J., Siber, G., 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.

    Article  CAS  PubMed  Google Scholar 

  • Bluestone, C.D., Stephenson, J.S., and Martin, L.M. (1992). Tenyear review of otitis media pathogens. Pediatr. Infect. Dis. J. 11, S7–11.

    Article  CAS  PubMed  Google Scholar 

  • Bokoch, G.M. (1995). Chemoattractant signaling and leukocyte activation. Blood 86, 1649–1660.

    CAS  PubMed  Google Scholar 

  • Bossink, A.W., Paemen, L., Jansen, P.M., Hack, C.E., Thijs, L.G., and Van Damme, J. (1995). Plasma levels of the chemokines monocyte chemotactic proteins-1 and -2 are elevated in human sepsis. Blood 86, 3841–3847.

    CAS  PubMed  Google Scholar 

  • Braun, J.S., Novak, R., Gao, G., Murray, P.J., and Shenep, J.L. (1999). Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide production from macrophages. Infect. Immun. 67, 3750–3756.

    CAS  PubMed  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.

    CAS  PubMed  Google Scholar 

  • Bruyn, G.A., and van Furth, R. (1991). Pneumococcal polysaccharide vaccines: indications, efficacy and recommendations. Eur. J. Clin. Microbiol. Infect. Dis. 10, 897–910.

    Article  CAS  PubMed  Google Scholar 

  • Bueno, O.F., De Windt, L.J., Lim, H.W., Tymitz, K.M., Witt, S.A., Kimball, T.R., and Molkentin, J.D. (2001). The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo. Circ. Res. 88, 88–96.

    CAS  PubMed  Google Scholar 

  • Camps, M., Nichols, A., and Arkinstall, S. (2000). Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 14, 6–16.

    CAS  PubMed  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.

    CAS  PubMed  Google Scholar 

  • Chi, H., Barry, S.P., Roth, R.J., Wu, J.J., Jones, E.A., Bennett, A.M., and Flavell, R.A. (2006). Dynamic regulation of pro- and antiinflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc. Natl. Acad. Sci. USA 103, 2274–2279.

    Article  CAS  PubMed  Google Scholar 

  • Cockeran, R., Steel, H.C., Mitchell, T.J., Feldman, C., and Anderson, R. (2001). Pneumolysin potentiates production of prostaglandin E(2) and leukotriene B(4) by human neutrophils. Infect. Immun. 69, 3494–3496.

    Article  CAS  PubMed  Google Scholar 

  • Cockeran, R., Durandt, C., Feldman, C., Mitchell, T.J., and Anderson, R. (2002). Pneumolysin activates the synthesis and release of interleukin-8 by human neutrophils in vitro. J. Infect. Dis. 186, 562–565.

    Article  CAS  PubMed  Google Scholar 

  • Cundell, D.R., Gerard, N.P., Gerard, C., Idanpaan-Heikkila, I., and Tuomanen, E.I. (1995). Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 377, 435–438.

    Article  CAS  PubMed  Google Scholar 

  • Dunzendorfer, S., Kaneider, N.C., Kaser, A., Woell, E., Frade, J.M., Mellado, M., Martinez-Alonso, C., and Wiedermann, C.J. (2001). Functional expression of chemokine receptor 2 by normal human eosinophils. J. Allergy Clin. Immunol. 108, 581–587.

    Article  CAS  PubMed  Google Scholar 

  • Folkard, S.G., Westwick, J., and Millar, A.B. (1997). Production of interleukin-8, RANTES and MCP-1 in intrinsic and extrinsic asthmatics. Eur. Respir. J. 10, 2097–2104.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  Google Scholar 

  • Gautam, S.C., Noth, C.J., Janakiraman, N., Pindolia, K.R., and Chapman, R.A. (1995). Induction of chemokine mRNA in bone marrow stromal cells: modulation by TGF-beta 1 and IL-4. Exp. Hematol. 23, 482–491.

    CAS  PubMed  Google Scholar 

  • Gu, L., Okada, Y., Clinton, S.K., Gerard, C., Sukhova, G.K., Libby, P., and Rollins, B.J. (1998). Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol. Cell 2, 275–281.

    Article  CAS  PubMed  Google Scholar 

  • Gu, L., Tseng, S.C., and Rollins, B.J. (1999). Monocyte chemoattractant protein-1. Chem. Immunol. 72, 7–29.

    Article  CAS  PubMed  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 IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent upregulation of MUC5AC mucin transcription by Streptococcus pneumoniae. J. Immunol. 178, 1736–1747.

    CAS  PubMed  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.

    Article  CAS  PubMed  Google Scholar 

  • Hausdorff, W.P., Bryant, J., Kloek, C., Paradiso, P.R., and Siber, G.R. (2000a). The contribution of specific pneumococcal serogroups to different disease manifestations: implications for conjugate vaccine formulation and use, part II. Clin. Infect. Dis. 30, 122–140.

    Article  CAS  PubMed  Google Scholar 

  • Hausdorff, W.P., Bryant, J., Paradiso, P.R., and Siber, G.R. (2000b). Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin. Infect. Dis. 30, 100–121.

    Article  CAS  PubMed  Google Scholar 

  • Heinemann, A., Hartnell, A., Stubbs, V.E., Murakami, K., Soler, D., LaRosa, G., Askenase, P.W., Williams, T.J., and Sabroe, I. (2000). Basophil responses to chemokines are regulated by both sequential and cooperative receptor signaling. J. Immunol. 165, 7224–7233.

    CAS  PubMed  Google Scholar 

  • Houldsworth, S., Andrew, P.W., and Mitchell, T.J. (1994). Pneumolysin stimulates production of tumor necrosis factor alpha and interleukin-1 beta by human mononuclear phagocytes. Infect. Immun. 62, 1501–1503.

    CAS  PubMed  Google Scholar 

  • Hutter, D., Chen, P., Barnes, J., and Liu, Y. (2000). Catalytic activation of mitogen-activated protein (MAP) kinase phosphatase-1 by binding to p38 MAP kinase: critical role of the p38 Cterminal domain in its negative regulation. Biochem. J. 352, 155–163.

    Article  CAS  PubMed  Google Scholar 

  • Jedrzejas, M.J. (2001). Pneumococcal virulence factors: structure and function. Microbiol. Mol. Biol. Rev. 65, 187–207; first page, table of contents.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, Y., Beller, D.I., Frendl, G., and Graves, D.T. (1992). Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J. Immunol. 148, 2423–2428.

    CAS  PubMed  Google Scholar 

  • Kalin, M. (1998). Pneumococcal serotypes and their clinical relevance. Thorax 53, 159–162.

    Article  CAS  PubMed  Google Scholar 

  • Kaminska, B. (2005). MAPK signalling pathways as molecular targets for anti-inflammatory therapy—from molecular mechanisms to therapeutic benefits. Biochim. Biophys. Acta 1754, 253–262.

    CAS  PubMed  Google Scholar 

  • Keyse, S.M. (2000). Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr. Opin. Cell Biol. 12, 186–192.

    Article  CAS  PubMed  Google Scholar 

  • Keyse, S.M. and Emslie, E.A. (1992). Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359, 644–647.

    Article  CAS  PubMed  Google Scholar 

  • Khreiss, T., Jozsef, L., Potempa, L.A., and Filep, J.G. (2004). Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation 109, 2016–2022.

    Article  CAS  PubMed  Google Scholar 

  • Kim, H.K., Lee, J.J., Lee, J.S., Park, Y.M., and Yoon, T.R. (2008). Rosmarinic acid down-regulates the LPS-induced production of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1alpha) via the MAPK pathway in bone-marrow derived dendritic cells. Mol. Cells 26, 583–589.

    CAS  PubMed  Google Scholar 

  • Lee, S.A., Fitzgerald, S.M., Huang, S.K., Li, C., Chi, D.S., Milhorn, D.M., and Krishnaswamy, G. (2004). Molecular regulation of interleukin-13 and monocyte chemoattractant protein-1 expression in human mast cells by interleukin-1beta. Am. J. Respir. Cell Mol. Biol. 31, 283–291.

    Article  CAS  PubMed  Google Scholar 

  • Lee, S.K., Choi, B.K., Kang, W.J., Kim, Y.H., Park, H.Y., Kim, K.H., and Kwon, B.S. (2008). MCP-1 derived from stromal keratocyte induces corneal infiltration of CD4+ T cells in herpetic stromal keratitis. Mol. Cells 26, 67–73.

    CAS  PubMed  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.

    Article  CAS  PubMed  Google Scholar 

  • Li, Q., Estepa, G., Memet, S., Israel, A., and Verma, I.M. (2000). Complete lack of NF-kappaB activity in IKK1 and IKK2 doubledeficient mice: additional defect in neurulation. Genes Dev. 14, 1729–1733.

    CAS  PubMed  Google Scholar 

  • Lin, Y., Zhang, M., and Barnes, P.F. (1998). Chemokine production by a human alveolar epithelial cell line in response to Mycobacterium tuberculosis. Infect. Immun. 66, 1121–1126.

    CAS  PubMed  Google Scholar 

  • Loetscher, P., Seitz, M., Clark-Lewis, I., Baggiolini, M., and Moser, B. (1996). Activation of NK cells by CC chemokines. Chemotaxis, Ca2+ mobilization, and enzyme release. J. Immunol. 156, 322–327.

    CAS  PubMed  Google Scholar 

  • Loghmani, F., Mohammed, K.A., Nasreen, N., Van Horn, R.D., Hardwick, J.A., Sanders, K.L., and Antony, V.B. (2002). Inflammatory cytokines mediate C-C (monocyte chemotactic protein 1) and C-X-C (interleukin 8) chemokine expression in human pleural fibroblasts. Inflammation 26, 73–82.

    Article  CAS  PubMed  Google Scholar 

  • Luster, A.D. (1998). Chemokines—chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 338, 436–445.

    Article  CAS  PubMed  Google Scholar 

  • Madsen, M., Lebenthal, Y., Cheng, Q., Smith, B.L., and Hostetter, M.K. (2000). A pneumococcal protein that elicits interleukin-8 from pulmonary epithelial cells. J. Infect. Dis. 181, 1330–1336.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Mitchell, T.J., and Andrew, P.W. (1997). Biological properties of pneumolysin. Microb. Drug Resist. 3, 19–26.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Paton, J.C., Berry, A.M., and Lock, R.A. (1997). Molecular analysis of putative pneumococcal virulence proteins. Microb. Drug Resist. 3, 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Price, K.E., and Camilli, A. (2009). Pneumolysin localizes to the cell wall of Streptococcus pneumoniae. J. Bacteriol. 191, 2163–2168.

    Article  CAS  PubMed  Google Scholar 

  • Pype, J.L., Dupont, L.J., Menten, P., Van Coillie, E., Opdenakker, G., Van Damme, J., Chung, K.F., Demedts, M.G., and Verleden, G.M. (1999). Expression of monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 by human airway smooth-muscle cells. Modulation by corticosteroids and T-helper 2 cytokines. Am. J. Respir. Cell Mol. Biol. 21, 528–536.

    CAS  PubMed  Google Scholar 

  • Reape, T.J., and Groot, P.H. (1999). Chemokines and atherosclerosis. Atherosclerosis 147, 213–225.

    Article  CAS  PubMed  Google Scholar 

  • Rijneveld, A.W., van den Dobbelsteen, G.P., Florquin, S., Standiford, T.J., Speelman, P., van Alphen, L., and van der Poll, T. (2002). Roles of interleukin-6 and macrophage inflammatory protein-2 in pneumolysin-induced lung inflammation in mice. J. Infect. Dis. 185, 123–126.

    Article  CAS  PubMed  Google Scholar 

  • Rosenow, C., Ryan, P., Weiser, J.N., Johnson, S., Fontan, P., Ortqvist, A., and Masure, H.R. (1997). Contribution of novel choline-binding proteins to adherence, colonization and immunogenicity of Streptococcus pneumoniae. Mol. Microbiol. 25, 819–829.

    Article  CAS  PubMed  Google Scholar 

  • Salojin, K.V., Owusu, I.B., Millerchip, K.A., Potter, M., Platt, K.A., and Oravecz, T. (2006). Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J. Immunol. 176, 1899–1907.

    CAS  PubMed  Google Scholar 

  • Sironi, M., Munoz, C., Pollicino, T., Siboni, A., Sciacca, F.L., Bernasconi, S., Vecchi, A., Colotta, F., and Mantovani, A. (1993). Divergent effects of interleukin-10 on cytokine production by mononuclear phagocytes and endothelial cells. Eur. J. Immunol. 23, 2692–2695.

    Article  CAS  PubMed  Google Scholar 

  • Sousa, A.R., Lane, S.J., Nakhosteen, J.A., Yoshimura, T., Lee, T.H., and Poston, R.N. (1994). Increased expression of the monocyte chemoattractant protein-1 in bronchial tissue from asthmatic subjects. Am. J. Respir. Cell. Mol. Biol. 10, 142–147.

    CAS  PubMed  Google Scholar 

  • Spratt, B.G., and Greenwood, B.M. (2000). Prevention of pneumococcal disease by vaccination: does serotype replacement matter? Lancet 356, 1210–1211.

    Article  CAS  PubMed  Google Scholar 

  • Tuomanen, E., Liu, H., Hengstler, B., Zak, O., and Tomasz, A. (1985). The induction of meningeal inflammation by components of the pneumococcal cell wall. J. Infect. Dis. 151, 859–868.

    CAS  PubMed  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.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zhu, J.F., Valente, A.J., Lorenzo, J.A., Carnes, D., and Graves, D.T. (1994). Expression of monocyte chemoattractant protein 1 in human osteoblastic cells stimulated by proinflammatory mediators. J. Bone Miner. Res. 9, 1123–1130.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Hee-Sung Shin, In-Hwa Yoo, Yong-Jae Kim, Hyong-Bai Kim & Un-Hwan Ha

  2. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Ji-Yun Lee

  3. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, 32610, USA

    Shouguang Jin

Authors
  1. Hee-Sung Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. In-Hwa Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-Jae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ji-Yun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyong-Bai Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shouguang Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Un-Hwan Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Un-Hwan Ha.

Additional information

These authors contributed equally to this work.

About this article

Cite this article

Shin, HS., Yoo, IH., Kim, YJ. et al. MKP1 regulates the induction of MCP1 by Streptococcus pneumoniae pneumolysin in human epithelial cells. Mol Cells 30, 263–270 (2010). https://doi.org/10.1007/s10059-010-0113-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10059-010-0113-0

Keywords

Search

Navigation