Skip to main content
Log in

Signaling networks controlling mucin production in response to Gram-positive and Gram-negative bacteria

  • Published:
Glycoconjugate Journal Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Human lung cells exposed to pathogenic bacteria upregulate the production of mucin, the major macromolecular component of mucus. Generally this upregulation is beneficial for the host, however, in the lungs of cystic fibrosis patients, overproduction of mucin can lead to the plugging of pulmonary airways. Mucus plugging impedes airflow and creates an environment that is highly compartmentalized: those bacteria within the mucus layer are shielded from high doses of antibiotics whereas those outside the mucus are exposed. These conditions augment mutation rate and the development of drug resistance in bacteria that colonize the lungs of cystic fibrosis patients. While therapeutic inhibition of mucin induction would improve airflow and reduce antibiotic resistance in these patients, the challenge is to develop drugs that block excessive mucin production while leaving beneficial aspects of the response intact. To do this, we must understand the molecular mechanisms underlying mucin production. Here we review the signal transduction pathways that control mucin production in response to Gram-positive and Gram-negative bacteria.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Webb DC, McKenzie AN, Koskinen AM, Yang M, Mattes J, Foster PS, Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity, J Immunol 165, 108–13 (2000).

    Google Scholar 

  2. Holt PG, Macaubas C, Stumbles PA, Sly PD, The role of allergy in the development of asthma, Nature 402, B12–7 (1999).

    Google Scholar 

  3. Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB, Requirement for IL-13 independently of IL-4 in experimental asthma, Science 282, 2261–3 (1998).

    Google Scholar 

  4. Coles SJ, Levine LR, Reid L, Hypersecretion of mucus glycoproteins in rat airways induced by tobacco smoke, Am J Pathol 94, 459–71 (1979).

    Google Scholar 

  5. Janus ED, Phillips NT, Carrell RW, Smoking, lung function, and alpha 1-antitrypsin deficiency, Lancet 1, 152–4 (1985).

    Google Scholar 

  6. Black LF, Kueppers F, Alpha1-antitrypsin deficiency in nonsmokers, Am Rev Respir Dis 117, 421–8 (1978).

    Google Scholar 

  7. Gadek JE, Fells GA, Crystal RG, Cigarette smoking induces functional antiprotease deficiency in the lower respiratory tract of humans, Science 206, 1315–6 (1979).

    Google Scholar 

  8. Hunninghake GW, Crystal RG, Cigarette smoking and lung destruction. Accumulation of neutrophils in the lungs of cigarette smokers, Am Rev Respir Dis 128, 833–8 (1983).

    Google Scholar 

  9. O'shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK, Inflammation in bronchial biopsies of subjects with chronic bronchitis: Inverse relationship of CD8+ T lymphocytes with FEV1, Am J Respir Crit Care Med 155, 852–7 (1997).

    Google Scholar 

  10. Majo J, Ghezzo H, Cosio MG, Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema, Eur Respir J 17, 946–53 (2001).

    Google Scholar 

  11. Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, Maestrelli P, Ciaccia A, Fabbri LM, CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease, Am J Respir Crit Care Med 157, 822–6 (1998).

    Google Scholar 

  12. Oliver A, Canton R, Campo P, Baquero F, Blazquez J, High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection, Science 288, 1251–4 (2000).

    Google Scholar 

  13. Collins F, Wilson J, A welcome animal model, Nature 358, 708–9 (1992).

    Google Scholar 

  14. Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB, Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease, Proc Natl Acad Sci USA 94, 967–72 (1997).

    Google Scholar 

  15. McNamara N, Khong A, McKemy D, Caterina M, Boyer J, Julius D, Basbaum C, ATP transduces signals from ASGM1, a glycolipid that functions as a bacterial receptor, Proc Natl Acad Sci USA 98, 9086–91 (2001).

    Google Scholar 

  16. Lemjabbar H, Basbaum C, Platelet-activating factor and ADAM 10 mediate responses to Staphlococcus aureus in epithelial cells, Nature Medicine 8, 41–6 (2002).

    Google Scholar 

  17. Diamond G, Russell JP, Bevins CL, Inducible expression of an antibiotic peptide gene in lipopolysaccharide-challenged tracheal epithelial cells, Proc Natl Acad Sci USA 93, 5156–60 (1996).

    Google Scholar 

  18. DiMango E, Zar H, Bryan R, Prince A, Diverse Pseudomonas gene products stimulate respiratory epithelial cells to produce interleukin-8, J Clin Invest 96, 2204–10 (1995).

    Google Scholar 

  19. Levine SJ, Larivee P, Logun C, Angus CW, Ognibene FP, Shelhamer JH, Tumor necrosis factor-alpha induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells, Am J Respir Cell Mol Biol 12, 196–204 (1995).

    Google Scholar 

  20. Kuan SF, Basbaum C, Byrd J, Kim Y, Characterization of high and low mucin variants from colon tumor cell line LS174T, Cancer Research 47, 5715–24 (1987).

    Google Scholar 

  21. Li JD, Feng W, Gallup M, Kim JH, Gum J, Kim Y, Basbaum C, Activation of NF-kappaB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa-induced mucin overproduction in epithelial cells, Proc Natl Acad Sci USA 95, 5718–23 (1998).

    Google Scholar 

  22. Natarajan K, Singh S, Burke T, Grunberger D, Aggarwal B, Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NFkB, Proc Natl Acad Sci USA 93, 9090–5 (1996).

    Google Scholar 

  23. Treisman R, Regulation of transcription by MAP kinase cascades, Curr Opin Cell Biol 8, 205–15 (1996).

    Google Scholar 

  24. Stokoe D, Campbell DG, Nakielny S, Hidaka H, Leevers SJ, Marshall C, Cohen P, MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase, EMBO J 11, 3985–94 (1992).

    Google Scholar 

  25. Howe L, Leevers S, Gomez N, Nakielny S, Cohen P, Marshall C, Activation of the MAP kinase pathway by the protein kinase raf, Cell 71, 335–42 (1992).

    Google Scholar 

  26. Moodie S, Willumsen B, Weber M, Wolfman A, Complexes of Ras. GTP with raf-1 and mitogen-activated protein kinase, Science 260, 1658–61 (1993).

    Google Scholar 

  27. Wood KW, Sarnecki C, Roberts TM, Blenis J, Ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK, Cell 68, 1041–50 (1992).

    Google Scholar 

  28. Katz ME, McCormick F, Signal transduction from multiple Ras effectors, Curr Opin Genet Dev 7, 75–9 (1997).

    Google Scholar 

  29. Feig LA, Cooper GM, Relationship among guanine nucleotide exchange, GTP hydrolysis, and transforming potential of mutated ras proteins, Mol Cell Biol 8, 2472–8 (1988).

    Google Scholar 

  30. Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP, Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation, Nature 375, 577–81 (1995).

    Google Scholar 

  31. Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, Pollok BA, Connelly PA, Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck-and FynT-dependent T cell activation, J Biol Chem 271, 695–701 (1996).

    Google Scholar 

  32. Weinstein S, Sanghera J, Lemke K, DeFranco A, Pelech S, Bacterial liposaccharide induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in macrophages, J Biol Chem 267, 14955–62 (1992).

    Google Scholar 

  33. Feldman M, Bryan R, Rajan S, Scheffler L, Brunnert S, Tang H, Prince A, Role of flagella in pathogenesis of Pseudomonas aeruginosa pulmonary infection, Infect Immun 66, 43–51 (1998).

    Google Scholar 

  34. Gum JR, Hicks JW, Kim YS, Identification and characterization of the MUC2 (human intestinal mucin) gene 5'-flanking region: Promoter activity in cultured cells, Biochem J 325, 259–67 (1997).

    Google Scholar 

  35. Segal ED, Lange C, Covacci A, Tompkins LS, Falkow S, Induction of host signal transduction pathways by Helicobacter pylori, Proc Natl Acad Sci USA 94, 7595–9 (1997).

    Google Scholar 

  36. Wilsson A, Lundqvist H, Gustafsson M, Stendahl O, Killing of phagocyosed Staphylococcus aureus by human neutrophils requires intracellular free calcium, Journal of Leukocyte Biology 59, 902–7 (1996).

    Google Scholar 

  37. Berridge MJ, Inositol trisphosphate and calcium signalling, Nature 361, 315–25 (1993).

    Google Scholar 

  38. Sekar MC, Hokin LE, The role of phosphoinositides in signal transduction, J Membr Biol 89, 193–210 (1986).

    Google Scholar 

  39. Harden TK, G-protein-regulated phospholipase C. Identification of component proteins, Adv Second Messenger Phosphoprotein Res 26, 11–34 (1992).

    Google Scholar 

  40. Cressman VL, Lazarowski E, Homolya L, Boucher RC, Koller BH, Grubb BR, Effect of loss of P2Y(2) receptor gene expression on nucleotide regulation of murine epithelial Cl(-) transport, J Biol Chem 274, 26461–8 (1999).

    Google Scholar 

  41. Homolya L, Watt WC, Lazarowski ER, Koller BH, Boucher RC, Nucleotide-regulated calcium signaling in lung fibroblasts and epithelial cells from normal and P2Y(2) receptor (?/?) mice, J Biol Chem 274, 26454–60 (1999).

    Google Scholar 

  42. North RA, Barnard EA, Nucleotide receptors, Curr Opin Neurobiol 7, 346–57 (1997).

    Google Scholar 

  43. Rice WR, Singleton FM, Reactive blue 2 selectively inhibits P2ypurinoceptor-stimulated surfactant phospholipid secretion from rat isolated alveolar type II cells, Br J Pharmacol 97, 158–62 (1989).

    Google Scholar 

  44. Tuluc F, Bultmann R, Glanzel M, Frahm AW, Starke K, P2-receptor antagonists: IV. Blockade of P2-receptor subtypes and ectonucleotidases by compounds related to reactive blue 2, Naunyn Schmiedebergs Arch Pharmacol 357, 111–20 (1998).

    Google Scholar 

  45. Abraham EH, Prat AG, Gerweck L, Seneveratne T, Arceci RJ, Kramer R, Guidotti G, Cantiello HF, The multidrug resistance (mdr1) gene product functions as an ATP channel, Proc Natl Acad Sci USA 90, 312–6 (1993).

    Google Scholar 

  46. Reisin IL, Prat AG, Abraham EH, Amara JF, Gregory RJ, Ausiello DA, Cantiello HF, The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel, J Biol Chem 269, 20584–91 (1994).

    Google Scholar 

  47. Reddy MM, Quinton PM, Haws C, Wine JJ, Grygorczyk R, Tabcharani JA, Hanrahan JW, Gunderson KL, Kopito RR, Failure of the cystic fibrosis transmembrane conductance regulator to conduct ATP, Science 271, 1876–9 (1996).

    Google Scholar 

  48. Salyers AA, Whitt DD, Bacterial Pathogenesis a Molecular Approach (ASM Press, Washington, DC, 1994), p. 341.

    Google Scholar 

  49. Cundell D, Gerard N, Gerard C, Idanpaan-Heikkila I, Tuomanen E, Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor, Nature 377, 435–8 (1995).

    Google Scholar 

  50. Cundell D, Gerard C, Idanpaan-Heikkala I, Tuomanen E, Gerard N, PAF receptor anchors Streptococcus pneumoniae to activated human endothelial cells, Adv Exp Med and Biol 416, 89–94 (1996).

    Google Scholar 

  51. Daub H, Weiss FU, Wallasch C, Ullrich A, Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors, Nature 379, 557–60 (1996).

    Google Scholar 

  52. Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, Ullrich A, EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF, Nature 402, 884–8 (1999).

    Google Scholar 

  53. Maudsley S, Pierce KL, Zamah AM, Miller WE, Ahn S, Daaka Y, Lefkowitz RJ, Luttrell LM, The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor, J Biol Chem 275, 9572–80 (2000).

    Google Scholar 

  54. Summerton J, Weller D, Morpholino antisense oligomers: Design, preparation, and properties, Antisense Nucleic Acid Drug Dev 7, 187–95 (1997).

    Google Scholar 

  55. Aderem A, Ulevitch, R, Toll-like receptors in the induction of the innate immune response, Nature 406, 782–7 (2000).

    Google Scholar 

  56. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning C, Peptidoglycan and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2, J Biol Chem 274, 17406 (1999).

    Google Scholar 

  57. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S, Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cellwall components, Immunity 11, 443–51 (1999).

    Google Scholar 

  58. Michelsen K, Aicher A, Mohaupt M, Hartung T, Dimmeler S, Kirschning C, Schumann R, Role of Toll-like receptors in bacteriainduced maturation of murine dencritic cells, J Biol Chem 276, 25680–6 (2001).

    Google Scholar 

  59. Opitz B, Schroder N, Spreitzer I, Michelsen K, Kirschning C, Hallatschek W, Zahringer U, Hartung T, Gobel U, Schumann R, Toll-like receptor 2 mediates Treponema glycolipid and lipoteichoic acid-induced NFkB translocation, J Biol Chem 276, 22041–7 (2001).

    Google Scholar 

  60. Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, Janeway CA Jr, MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways, Mol Cell 2, 253–8 (1998).

    Google Scholar 

  61. Hovenberg H, Davies J, Carlstedt I, Different mucins are produced by the surface epithelium and submucosa in human trachea: Identification of MUC 5 AC as a major mucin from the goblet cells, Biochem J 318, 319–24 (1996).

    Google Scholar 

  62. Gendler S, Madsen C, Aust M, Yankaskas J, Jennings J, Kasperbauer J, Expression of mucin genes in human cystic fibrosis and control sinus and lung tissues, Pediatric Pulmonology 13S, 290 (Abstract) (1996).

    Google Scholar 

  63. Dohrman A, Miyata S, Gallup M, Li JD, Chapelin C, Coste A, Escudier E, Nadel J, Basbaum C, Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria, Biochim Biophys Acta 1406, 251–9 (1998).

    Google Scholar 

  64. Li D, Gallup M, Fan N, Szymkowski D, Basbaum C, Cloning of the amino terminal and 5’ flanking region of the human MUC 5 AC mucin gene and transcriptional upregulation by bacterial exoproducts, J Biol Chem 273, 6812–20 (1998).

    Google Scholar 

  65. Lapin JH, Whooping Cough (Thomas, Springfield, IL, 1943).

    Google Scholar 

  66. Belcher CE, Drenkow J, Kehoe B, Gingeras TR, McNamara N, Lemjabbar H, Basbaum C, Relman DA, From the cover: The transcriptional responses of respiratory epithelial cells to Bordetella pertussis reveal host defensive and pathogen counter-defensive strategies, Proc Natl Acad Sci USA 97, 13847–52 (2000).

    Google Scholar 

  67. Kuklinska D, Kilian M, Relative proportions of Haemophilus species in the throat of healthy children and adults, Eur J Clin Microbiol 3, 249–52 (1984).

    Google Scholar 

  68. Moxon ER, The carrier state: Haemophilus influenzae, J Antimicrob Chemother 18 (Suppl A), 17–24 (1986).

    Google Scholar 

  69. Wang B, Lim DJ, Han J, Kim YS, Basbaum CB, Li JD, Novel cytoplasmic proteins of nontypeable Haemophilus influenzae upregulate human MUC5AC mucin transcription via a positive p38 mitogen-activated protein kinase pathway and a negative phosphoinositide 3-kinase-Akt pathway, J Biol Chem 277, 949–57 (2002).

    Google Scholar 

  70. Medzhitov R, Janeway CA Jr, An ancient system of host defense, Curr Opin Immunol 10, 12–15 (1998).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

McNamara, N., Basbaum, C. Signaling networks controlling mucin production in response to Gram-positive and Gram-negative bacteria. Glycoconj J 18, 715–722 (2001). https://doi.org/10.1023/A:1020875423678

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020875423678

Navigation