Mucin expression in CF via TLRs, EGFR signaling pathways

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Mucin expression in CF via TLRs, EGFR signaling pathways

Cystic Fibrosis (CF) is a potentially lethal genetic disease that typically results in the development of bronchial inflammation, bronchiectasis, the progressive loss of lung function and ultimately death [1].

CF was initially called "mucoviscidosis" because of copious amounts of "mucoproteins" in the respiratory and gastrointestinal tracts of CF patients [2].

CF is a recessive genetic disease caused by mutations in the CFTR gene, which encodes the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a chloride channel. Expression of mutant CFTR in CF respiratory cells results in defective chloride secretion and elevated sodium absorption, resulting in altered salt concentrations in airway secretions. Alterations in mucus volume may impact mucus hydration, and thus the rheology of CF airway mucus to increase susceptibility to infection in CF airways. Lack of functional CFTR in lung cells could engender a hyperinflammatory state that alters homeostasis in CF airways. Inflammatory mediators in the airways of CF can increase expression of mucin genes, contributing to recurring cycles of infection followed by increased expression of mucins that culminates in airway obstruction with mucus [2].

Pseudomonas aeruginosa is the predominant pathogen of CF chronic lung infection [3]. Reduced secretion of chloride and fluid hydration, as well as excessive secretion of mucins, produce a biological matrix that facilitates growth of P. aeruginosa in biofilm [1].

Secretory mucus/gel-forming mucins (Mucin 2, Mucin 5AC, and Mucin 5B) are secreted by airway mucus-secreting cells. The mucins are subject to regulation by CF inflammatory stimuli. Mucin 5AC and Mucin 5B have been identified as major gel-forming macromolecules; whereas Mucin 2 contributes only to a lesser extend to the matrix [2].

In normal human airways, Mucin 5AC is mainly expressed in surface goblet epithelial cells, whereas Mucin 5B is predominantly expressed in mucous cells of submucosal glands and Mucin 2 is weakly expressed in both cell types [2], [4], [5], [6], [7]. However, Mucin 5B gene products in diseased airways (e.g. in CF or asthma) are also found in the surface epithelium, rather than just being limited to the submucosal glands [6], [8], [9], [10]. Expression of Mucin 5B might be a result of goblet cell hyperplasia and mucus hypersecretion associated with various airway diseases [6], [9], [11].

A wide variety of stimuli present in the airways of patients with CF (e.g. Pseudomonas aeruginosa components and proinflammatory cytokines) are known to cause mucin overproduction.

P. aeruginosa components transcriptionally upregulate Mucin 2 gene expression [12], [13]. P. aeruginosa products have also been reported to upregulate Mucin 5AC expression [14]. The ultimate step leading to Mucin 2 or Mucin 5AC gene upregulation is the activation of several transcription factors including Nuclear Factor kappa-B (NF-kB), Activator protein 1 (AP-1) that is mainly composed of c-Jun and c-Fos (c-Jun/c-Fos heterodimer), and Sp1 transcription factor (SP1) [15].

Flagellin (P. aeruginosa) and P. aeruginosa component pilin (PilA (P. aeruginosa)) are recognized by the surface receptors, asialo-GM1 ganglioside (asialo-ganglioside GA1) and Toll-like receptors (TLRs) [3], [16], [17].

Flagellin (P. aeruginosa) is recognized by TLR5 [3]. Flagellin (P. aeruginosa) [13] and PilA (P. aeruginosa) [18] bind bacteria to the host cell glycolipid receptor, asialo-ganglioside GA1. The TLR2-asialo-ganglioside GA1 complex in response to P. aeruginosa induces the activation of NF-kB, initiates the proinflammatory signaling and stimulates transcription of Mucin 2 [13].

TLRs activate the canonical NF-kB pathway: Myeloid differentiation primary response gene 88 (MyD88)/ Interleukin-1 receptor-associated kinases 4, 1 and 2 (IRAK4 and IRAK1/2)/ TNF Receptor-associated factor 6 (TRAF6)/ Mitogen-activated protein kinase kinase kinase 7 interacting proteins 1 and 2 (TAB1 and TAB2)/ Mitogen-activated protein kinase kinase kinase 7 (TAK1)/ Mitogen-activated protein kinase kinase kinase 14 (NIK)/ I-kB kinase complex (IKK(cat))/ Nuclear factor kappa-B inhibitor (I-kB)/ NF-kB [19], [20], [21]. TLR2 (or TLR4) signaling also requires an additional adaptor Toll-Interleukin 1 receptor domain containing adaptor protein (TIRAP) [22], [23].

P. aeruginosa has also been shown to activate another pathway: Tyrosine Kinase (c-Src)/ Harvey Rat Sarcoma Viral Oncogene Homolog (H-Ras)/ Murine Leukemia Viral Oncogene Homolog 1 (c-Raf-1)/ Mitogen-Activated Protein Kinase Kinase 1 and 2 (MEK1/2)/ Mitogen-Activated Protein Kinase 1 and 3 (ERK1/2)/ Ribosomal Protein S6 Kinase Alpha-1 (p90RSK1), which in turn leads to the activation of NF-kB and triggers Mucin 2 transcription [12], [24].

Epithelial responses to CF bacterial ligands mediated by TLRs also result in the NF-kB-induced transcription of Interleukin 6 (IL-6) involved in the expression of mucin genes [3].

Overproduction of mucin in the airways of patients with CF is also known to cause by Epidermal Growth Factor Receptor (EGFR) activation [25]. A prominent EGFR ligand, Transforming Growth Factor, Alpha (TGF-alpha), is markedly increased in the epithelium of patients with CF [26]. EGFR activates ERK1/2 cascade via SHC Transforming Protein 1 (Shc)/ Growth Factor Receptor-Bound Protein 2 (GRB2)/ Son of Sevenless Homolog 1 and 2 (SOS)/ H-Ras/ c-Raf-1/ MEK1/2 pathway [27], leading to the activation of c-Jun/c-Fos and SP1 transcription factors that can trigger Mucin 5AC and Mucin 2 transcription [10], [28], [29].

Unlike in the case of Mucin 2 and Mucin 5AC, little is known about the mechanisms of Mucin 5B expression. In human bronchial epithelial cell cultures, Mucin 5B expression is activated via an EGFR/ERK-independent Protein Kinase delta (PKC-delta), H-Ras, Mitogen-Activated Protein Kinase Kinase Kinase 1 (MEKK1)-mediated, c-Jun N-terminal kinase (JNK)/ Mitogen-Activated Protein Kinase 14 (p38alpha), SP1-dependent signaling pathway [10].

EGFR signaling could increase Mucin 5AC secretion in the airway CF epithelium, whereas Mucin 5B production is more prominent in the lumen of patients with CF [29].

References:

  1. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  2. Rose MC, Voynow JA
    Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiological reviews 2006 Jan;86(1):245-78
  3. Gomez MI, Prince A
    Opportunistic infections in lung disease: Pseudomonas infections in cystic fibrosis. Current opinion in pharmacology 2007 Jun;7(3):244-51
  4. Reid CJ, Gould S, Harris A
    Developmental expression of mucin genes in the human respiratory tract. American journal of respiratory cell and molecular biology 1997 Nov;17(5):592-8
  5. Copin MC, Devisme L, Buisine MP, Marquette CH, Wurtz A, Aubert JP, Gosselin B, Porchet N
    From normal respiratory mucosa to epidermoid carcinoma: expression of human mucin genes. International journal of cancer. Journal international du cancer 2000 Apr 15;86(2):162-8
  6. Groneberg DA, Eynott PR, Oates T, Lim S, Wu R, Carlstedt I, Nicholson AG, Chung KF
    Expression of MUC5AC and MUC5B mucins in normal and cystic fibrosis lung. Respiratory medicine 2002 Feb;96(2):81-6
  7. Hays SR, Fahy JV
    Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils. American journal of respiratory and critical care medicine 2006 Nov 1;174(9):1018-24
  8. Wickstrom C, Davies JR, Eriksen GV, Veerman EC, Carlstedt I
    MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: identification of glycoforms and C-terminal cleavage. The Biochemical journal 1998 Sep 15;334 ( Pt 3):685-93
  9. Chen Y, Zhao YH, Di YP, Wu R
    Characterization of human mucin 5B gene expression in airway epithelium and the genomic clone of the amino-terminal and 5'-flanking region. American journal of respiratory cell and molecular biology 2001 Nov;25(5):542-53
  10. Yuan-Chen Wu D, Wu R, Reddy SP, Lee YC, Chang MM
    Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate. The American journal of pathology 2007 Jan;170(1):20-32
  11. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R
    Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. The Journal of biological chemistry 2003 May 9;278(19):17036-43
  12. 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. Proceedings of the National Academy of Sciences of the United States of America 1997 Feb 4;94(3):967-72
  13. 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. Proceedings of the National Academy of Sciences of the United States of America 2001 Jul 31;98(16):9086-91
  14. Li D, Gallup M, Fan N, Szymkowski DE, Basbaum CB
    Cloning of the amino-terminal and 5'-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts. The Journal of biological chemistry 1998 Mar 20;273(12):6812-20
  15. Voynow JA, Gendler SJ, Rose MC
    Regulation of mucin genes in chronic inflammatory airway diseases. American journal of respiratory cell and molecular biology 2006 Jun;34(6):661-5
  16. Gibson RL, Burns JL, Ramsey BW
    Pathophysiology and management of pulmonary infections in cystic fibrosis. American journal of respiratory and critical care medicine 2003 Oct 15;168(8):918-51
  17. Adamo R, Sokol S, Soong G, Gomez MI, Prince A
    Pseudomonas aeruginosa flagella activate airway epithelial cells through asialoGM1 and toll-like receptor 2 as well as toll-like receptor 5. American journal of respiratory cell and molecular biology 2004 May;30(5):627-34
  18. Comolli JC, Waite LL, Mostov KE, Engel JN
    Pili binding to asialo-GM1 on epithelial cells can mediate cytotoxicity or bacterial internalization by Pseudomonas aeruginosa. Infection and immunity 1999 Jul;67(7):3207-14
  19. Li J, Johnson XD, Iazvovskaia S, Tan A, Lin A, Hershenson MB
    Signaling intermediates required for NF-kappa B activation and IL-8 expression in CF bronchial epithelial cells. American journal of physiology. Lung cellular and molecular physiology 2003 Feb;284(2):L307-15
  20. Soong G, Reddy B, Sokol S, Adamo R, Prince A
    TLR2 is mobilized into an apical lipid raft receptor complex to signal infection in airway epithelial cells. The Journal of clinical investigation 2004 May;113(10):1482-9
  21. Greene CM, McElvaney NG
    Toll-like receptor expression and function in airway epithelial cells. Archivum immunologiae et therapiae experimentalis 2005 Sep-Oct;53(5):418-27
  22. Takeda K, Akira S
    Microbial recognition by Toll-like receptors. Journal of dermatological science 2004 Apr;34(2):73-82
  23. Greene CM, Carroll TP, Smith SG, Taggart CC, Devaney J, Griffin S, O'neill SJ, McElvaney NG
    TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. Journal of immunology (Baltimore, Md. : 1950) 2005 Feb 1;174(3):1638-46
  24. 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. Proceedings of the National Academy of Sciences of the United States of America 1998 May 12;95(10):5718-23
  25. Burgel PR, Nadel JA
    Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 2004 Nov;59(11):992-6
  26. Hardie WD, Bejarano PA, Miller MA, Yankaskas JR, Ritter JH, Whitsett JA, Korfhagen TR
    Immunolocalization of transforming growth factor alpha and epidermal growth factor receptor in lungs of patients with cystic fibrosis. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 1999 Sep-Oct;2(5):415-23
  27. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A
    The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocrine-related cancer 2001 Mar;8(1):11-31
  28. Perrais M, Pigny P, Copin MC, Aubert JP, Van Seuningen I
    Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1. The Journal of biological chemistry 2002 Aug 30;277(35):32258-67
  29. Burgel PR, Montani D, Danel C, Dusser DJ, Nadel JA
    A morphometric study of mucins and small airway plugging in cystic fibrosis. Thorax 2007 Feb;62(2):153-61

  1. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  2. Rose MC, Voynow JA
    Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiological reviews 2006 Jan;86(1):245-78
  3. Gomez MI, Prince A
    Opportunistic infections in lung disease: Pseudomonas infections in cystic fibrosis. Current opinion in pharmacology 2007 Jun;7(3):244-51
  4. Reid CJ, Gould S, Harris A
    Developmental expression of mucin genes in the human respiratory tract. American journal of respiratory cell and molecular biology 1997 Nov;17(5):592-8
  5. Copin MC, Devisme L, Buisine MP, Marquette CH, Wurtz A, Aubert JP, Gosselin B, Porchet N
    From normal respiratory mucosa to epidermoid carcinoma: expression of human mucin genes. International journal of cancer. Journal international du cancer 2000 Apr 15;86(2):162-8
  6. Groneberg DA, Eynott PR, Oates T, Lim S, Wu R, Carlstedt I, Nicholson AG, Chung KF
    Expression of MUC5AC and MUC5B mucins in normal and cystic fibrosis lung. Respiratory medicine 2002 Feb;96(2):81-6
  7. Hays SR, Fahy JV
    Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils. American journal of respiratory and critical care medicine 2006 Nov 1;174(9):1018-24
  8. Wickstrom C, Davies JR, Eriksen GV, Veerman EC, Carlstedt I
    MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: identification of glycoforms and C-terminal cleavage. The Biochemical journal 1998 Sep 15;334 ( Pt 3):685-93
  9. Chen Y, Zhao YH, Di YP, Wu R
    Characterization of human mucin 5B gene expression in airway epithelium and the genomic clone of the amino-terminal and 5'-flanking region. American journal of respiratory cell and molecular biology 2001 Nov;25(5):542-53
  10. Yuan-Chen Wu D, Wu R, Reddy SP, Lee YC, Chang MM
    Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate. The American journal of pathology 2007 Jan;170(1):20-32
  11. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R
    Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. The Journal of biological chemistry 2003 May 9;278(19):17036-43
  12. 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. Proceedings of the National Academy of Sciences of the United States of America 1997 Feb 4;94(3):967-72
  13. 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. Proceedings of the National Academy of Sciences of the United States of America 2001 Jul 31;98(16):9086-91
  14. Li D, Gallup M, Fan N, Szymkowski DE, Basbaum CB
    Cloning of the amino-terminal and 5'-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts. The Journal of biological chemistry 1998 Mar 20;273(12):6812-20
  15. Voynow JA, Gendler SJ, Rose MC
    Regulation of mucin genes in chronic inflammatory airway diseases. American journal of respiratory cell and molecular biology 2006 Jun;34(6):661-5
  16. Gibson RL, Burns JL, Ramsey BW
    Pathophysiology and management of pulmonary infections in cystic fibrosis. American journal of respiratory and critical care medicine 2003 Oct 15;168(8):918-51
  17. Adamo R, Sokol S, Soong G, Gomez MI, Prince A
    Pseudomonas aeruginosa flagella activate airway epithelial cells through asialoGM1 and toll-like receptor 2 as well as toll-like receptor 5. American journal of respiratory cell and molecular biology 2004 May;30(5):627-34
  18. Comolli JC, Waite LL, Mostov KE, Engel JN
    Pili binding to asialo-GM1 on epithelial cells can mediate cytotoxicity or bacterial internalization by Pseudomonas aeruginosa. Infection and immunity 1999 Jul;67(7):3207-14
  19. Li J, Johnson XD, Iazvovskaia S, Tan A, Lin A, Hershenson MB
    Signaling intermediates required for NF-kappa B activation and IL-8 expression in CF bronchial epithelial cells. American journal of physiology. Lung cellular and molecular physiology 2003 Feb;284(2):L307-15
  20. Soong G, Reddy B, Sokol S, Adamo R, Prince A
    TLR2 is mobilized into an apical lipid raft receptor complex to signal infection in airway epithelial cells. The Journal of clinical investigation 2004 May;113(10):1482-9
  21. Greene CM, McElvaney NG
    Toll-like receptor expression and function in airway epithelial cells. Archivum immunologiae et therapiae experimentalis 2005 Sep-Oct;53(5):418-27
  22. Takeda K, Akira S
    Microbial recognition by Toll-like receptors. Journal of dermatological science 2004 Apr;34(2):73-82
  23. Greene CM, Carroll TP, Smith SG, Taggart CC, Devaney J, Griffin S, O'neill SJ, McElvaney NG
    TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. Journal of immunology (Baltimore, Md. : 1950) 2005 Feb 1;174(3):1638-46
  24. 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. Proceedings of the National Academy of Sciences of the United States of America 1998 May 12;95(10):5718-23
  25. Burgel PR, Nadel JA
    Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 2004 Nov;59(11):992-6
  26. Hardie WD, Bejarano PA, Miller MA, Yankaskas JR, Ritter JH, Whitsett JA, Korfhagen TR
    Immunolocalization of transforming growth factor alpha and epidermal growth factor receptor in lungs of patients with cystic fibrosis. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 1999 Sep-Oct;2(5):415-23
  27. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A
    The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocrine-related cancer 2001 Mar;8(1):11-31
  28. Perrais M, Pigny P, Copin MC, Aubert JP, Van Seuningen I
    Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1. The Journal of biological chemistry 2002 Aug 30;277(35):32258-67
  29. Burgel PR, Montani D, Danel C, Dusser DJ, Nadel JA
    A morphometric study of mucins and small airway plugging in cystic fibrosis. Thorax 2007 Feb;62(2):153-61

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