title: Loss of cystic fibrosis transmembrane conductance regulator function enhances activation of p38 and ERK MAPKs, increasing interleukin-6 synthesis in airway epithelial cells exposed to Pseudomonas aeruginosa.
abstract: In cystic fibrosis (CF), the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) translates into chronic bacterial infection, excessive inflammation, tissue damage, impaired lung function and eventual death. Understanding the mechanisms underlying this vicious circle of inflammation is important to design better therapies for CF. We found in CF lung biopsies increased immunoreactivity for p38 MAPK activity markers. Moreover, when compared with their non-CF counterpart, airway epithelial cells expressing the most common mutation in CF (CFTRDeltaF508) were more potent at inducing neutrophil chemotaxis through increased interleukin (IL)-6 synthesis when challenged with Pseudomonas aeruginosa diffusible material. We then discovered that in CFTRDeltaF508 cells, the p38 and ERK MAPKs are hyperactivated in response to P. aeruginosa diffusible material, leading to increased IL-6 mRNA expression and stability. Moreover, although TLR5 contributes to p38 MAPK activation upon P. aeruginosa challenge, it only played a weak role in IL-6 synthesis. Instead, we found that the production of reactive oxygen species is essential for IL-6 synthesis in response to P. aeruginosa diffusible material. Finally, we uncovered that in CFTRDeltaF508 cells, the extracellular glutathione levels are decreased, leading to a greater sensitivity to reactive oxygen species, providing an explanation for the hyperactivation of the p38 and ERK MAPKs and increased IL-6 synthesis. Taken together, our study has characterized a mechanism whereby the CFTRDeltaF508 mutation in airway epithelial cells contributes to increase inflammation of the airways.
authors.affiliation: Meakins-Christie Laboratories, McGill University Heath Centre Research Institute, Montréal, Québec H2X 2P2, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Bérubé
authors.forename: Lucie
authors.initials: L
authors.lastname: Roussel
authors.forename: Leila
authors.initials: L
authors.lastname: Nattagh
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
mesh_terms: D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D003550:Cystic Fibrosis / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology* / Q000382:microbiology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000166:cytology; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018121:Receptors, Cytokine; D051192:Receptors, Pattern Recognition; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione
references.citation: Am J Respir Crit Care Med. 1995 Dec;152(6 Pt 1):2111-8
references.pmid: 8520783
references.citation: Mol Cell. 2005 Dec 22;20(6):891-903
references.pmid: 16364914
references.citation: J Leukoc Biol. 2000 Dec;68(6):909-15
references.pmid: 11129660
references.citation: Free Radic Biol Med. 2000 Feb 1;28(3):463-99
references.pmid: 10699758
references.citation: Cell. 1990 Nov 16;63(4):827-34
references.pmid: 1699669
references.citation: Science. 2008 Aug 1;321(5889):691-6
references.pmid: 18669862
references.citation: Immunity. 1997 Dec;7(6):837-47
references.pmid: 9430229
references.citation: J Biol Chem. 2002 Feb 1;277(5):3065-8
references.pmid: 11741878
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Mol Cell Biol. 2005 Dec;25(23):10454-64
references.pmid: 16287858
references.citation: Am Rev Respir Dis. 1989 Dec;140(6):1650-61
references.pmid: 2513765
references.citation: Nat Immunol. 2006 Dec;7(12):1250-7
references.pmid: 17110941
references.citation: J Clin Invest. 1998 Sep 15;102(6):1200-7
references.pmid: 9739054
references.citation: Nature. 2006 May 11;441(7090):235-8
references.pmid: 16648838
references.citation: Chest. 2002 May;121(5 Suppl):136S-141S
references.pmid: 12010842
references.citation: Nature. 1996 Oct 3;383(6599):443-6
references.pmid: 8837778
references.citation: Curr Opin Immunol. 2006 Feb;18(1):3-9
references.pmid: 16343886
references.citation: Biochem J. 2007 Jun 1;404(2):179-90
references.pmid: 17348859
references.citation: Infect Immun. 2006 Jun;74(6):3115-24
references.pmid: 16714539
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Mar;280(3):L493-502
references.pmid: 11159033
references.citation: Am J Physiol. 1999 Mar;276(3):C700-10
references.pmid: 10069998
references.citation: J Allergy Clin Immunol. 1999 Jul;104(1):72-8
references.pmid: 10400842
references.citation: J Immunol. 2010 Apr 15;184(8):4531-7
references.pmid: 20228195
references.citation: Sci Signal. 2009 Oct 13;2(92):ra63
references.pmid: 19825828
references.citation: Inflammation. 2001 Jun;25(3):145-55
references.pmid: 11403205
references.citation: Am J Respir Crit Care Med. 2004 Mar 1;169(5):645-53
references.pmid: 14670800
references.citation: Clin Microbiol Rev. 2002 Apr;15(2):194-222
references.pmid: 11932230
references.citation: Nature. 1999 Mar 18;398(6724):252-6
references.pmid: 10094049
references.citation: EMBO J. 2002 Dec 2;21(23):6505-14
references.pmid: 12456657
references.citation: FEBS Lett. 1995 May 8;364(2):229-33
references.pmid: 7750577
references.citation: Cell Signal. 2009 Mar;21(3):448-56
references.pmid: 19121387
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15434-9
references.pmid: 14668439
references.citation: Science. 1997 Nov 28;278(5343):1612-5
references.pmid: 9374458
references.citation: Annu Rev Biochem. 2005;74:355-83
references.pmid: 15952891
references.citation: Cell Signal. 2008 Feb;20(2):375-80
references.pmid: 18065201
references.citation: Nature. 1990 Apr 12;344(6267):665-7
references.pmid: 1691449
references.citation: J Biol Chem. 2005 May 20;280(20):19472-9
references.pmid: 15755732
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1358-75
references.pmid: 17481747
references.citation: Nature. 1994 Dec 22-29;372(6508):739-46
references.pmid: 7997261
references.citation: Biochem Biophys Res Commun. 2008 Feb 8;366(2):513-9
references.pmid: 18073139
references.citation: J Biol Chem. 2001 Jun 1;276(22):19267-75
references.pmid: 11278360
references.citation: Cell. 1994 Sep 23;78(6):1027-37
references.pmid: 7923353
references.citation: J Biol Chem. 2004 Mar 12;279(11):10176-84
references.pmid: 14688255
references.citation: Am J Physiol. 1999 Jul;277(1):L113-8
references.pmid: 10409237
references.citation: Respir Res. 2005 Apr 01;6:26
references.pmid: 15804356
references.citation: EMBO J. 1996 Apr 15;15(8):1914-23
references.pmid: 8617238
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12230-4
references.pmid: 8618875