Role of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis airways

NF-kappa B; AP-1; transcription factors; inflammation; CFTR; gene expression; Mutation; Transcription Factor AP-1/metabolism; Trachea/cytology/embryology; Reverse Transcriptase Polymerase Chain Reaction; NF-kappa B/metabolism; Interleukin-8/metabolism; Models, Biological; Luciferases/metabolism; Cell Line, Transformed; Interleukin-6/metabolism; Inflammation/pathology; Interleukin-1beta/metabolism; I-kappa B Kinase/antagonists & inhibitors/metabolism; Homozygote; Humans; Genes, Reporter; Hela Cells; Fibroblast Growth Factor 2/metabolism; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism; Enzyme-Linked Immunosorbent Assay; Cystic Fibrosis Transmembrane Conductance Regulator/genetics; Chemokine CXCL1; Chemokine CXCL2; Chemokines, CXC/metabolism; Cystic Fibrosis/metabolism/pathology

Abstract :

[en] in cystic fibrosis (CF) patients, pulmonary inflammation is a major cause of morbidity and mortality and may precede bacterial colonization. The aim of the present study was to investigate the molecular mechanisms underlying intrinsic inflammation in cystic fibrosis air-ways. Using different cystic fibrosis cell models, we first demonstrated that, beside a high constitutive nuclear factor of kappaB (NF-kappa B) activity, CF cells showed a higher activator protein-1 (AP-1) activity as compared to their respective control cells. Gene expression profiles, confirmed by RT-PCR and ELISA, showed over-expression of numerous NF-KB and AP-1-dependent pro-inflammatory genes in CF cells in comparison with control cells. Activation of NF-KB was correlated with higher inhibitor of kappa B kinase (IKK) activity. In addition, Bio-plex phosphoprotein assays revealed higher extracellular signal-regulated kinase (ERK) phosphorylation in CFT-2 cells. Inhibition of this kinase strongly decreased expression of pro-inflammatory genes coding for growth-regulated proteins (Gro-alpha, Gro-beta and Gro-gamma) and interleukins (IL-1 beta, IL-6 and IL-8). Moreover, inhibition of secreted interleukin-1 beta (IL-1 beta) and basic fibroblast growth factor (bFGF) with neutralizing antibodies reduced pro-inflammatory gene expression. Our data thus demonstrated for the first time that the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) at the plasma membrane leads to an intrinsic AP-1, in addition to NF-kappa B, activity and consequently to a pro-inflammatory state sustained through autocrine factors such as IL-1 beta and bFGF. (c) 2007 Elsevier Inc. All rights reserved.

Research Center/Unit :

Giga-Signal Transduction - ULiège

Disciplines :

Pharmacy, pharmacology & toxicology
Biochemistry, biophysics & molecular biology

Author, co-author :

Verhaeghe, Catherine ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique générale et humaine

Remouchamps, Caroline ; Université de Liège - ULiège > Virologie - Immunologie

Hennuy, Benoît ; Université de Liège - ULiège > GIGA-Management : Plate-forme transcriptomique

Vanderplasschen, Alain ; Université de Liège - ULiège > Immunologie et vaccinologie

Chariot, Alain ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Tabruyn, Sébastien P

Oury, Cécile ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine

Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine

Language :

English

Title :

Role of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis airways

Publication date :

15 June 2007

Journal title :

Biochemical Pharmacology

ISSN :

0006-2952

eISSN :

1873-2968

Publisher :

Elsevier Science, Oxford, United Kingdom

Volume :

Issue :

Pages :

1982-1994

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique
Télévie
PAI

Available on ORBi :

since 06 January 2009

Statistics

Number of views

215 (19 by ULiège)

Number of downloads

55 (5 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Lyczak J.B., Cannon C.L., and Pier G.B. Lung infections associated with cystic fibrosis. Clin Microbiol Rev 15 (2002) 194-222
Chow C.W., Landau L.I., and Taussig L.M. Bronchial mucous glands in the newborn with cystic fibrosis. Eur J Pediatr 139 (1982) 240-243
Ornoy A., Arnon J., Katznelson D., Granat M., Caspi B., and Chemke J. Pathological confirmation of cystic fibrosis in the fetus following prenatal diagnosis. Am J Med Genet 28 (1987) 935-947
Verhaeghe C, Delbecque K, de Leval L, Oury C, Bours V. Early inflammation in the airways of a cystic fibrosis foetus. J Cyst Fibros; 2007.
Bonfield T.L., Konstan M.W., and Berger M. Altered respiratory epithelial cell cytokine production in cystic fibrosis. J Allergy Clin Immunol 104 (1999) 72-78
Khan T.Z., Wagener J.S., Bost T., Martinez J., Accurso F.J., and Riches D.W. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 151 (1995) 1075-1082
Noah T.L., Black H.R., Cheng P.W., Wood R.E., and Leigh M.W. Nasal and bronchoalveolar lavage fluid cytokines in early cystic fibrosis. J Infect Dis 175 (1997) 638-647
Mall M., Grubb B.R., Harkema J.R., O'Neal W.K., and Boucher R.C. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med 10 (2004) 487-493
Knorre A., Wagner M., Schaefer H.E., Colledge W.H., and Pahl H.L. DeltaF508-CFTR causes constitutive NF-kappaB activation through an ER-overload response in cystic fibrosis lungs. Biol Chem 383 (2002) 271-282
Venkatakrishnan A., Stecenko A.A., King G., Blackwell T.R., Brigham K.L., Christman J.W., et al. Exaggerated activation of nuclear factor-kappaB and altered IkappaB-beta processing in cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol 23 (2000) 396-403
Tabary O., Escotte S., Couetil J.P., Hubert D., Dusser D., Puchelle E., et al. Relationship between IkappaBalpha deficiency, NFkappaB activity and interleukin-8 production in CF human airway epithelial cells. Pflugers Arch 443 Suppl 1 (2001) S40-S44
DiDonato J.A., Hayakawa M., Rothwarf D.M., Zandi E., and Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388 (1997) 548-554
Armstrong D.S., Hook S.M., Jamsen K.M., Nixon G.M., Carzino R., Carlin J.B., et al. Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr Pulmonol 40 (2005) 500-510
Dakin C.J., Numa A.H., Wang H., Morton J.R., Vertzyas C.C., and Henry R.L. Inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 165 (2002) 904-910
Delacourt C. Inflammation and cystic fibrosis. Arch Pediatr 10 Suppl 2 (2003) 338s-341s
Medjane S., Raymond B., Wu Y., and Touqui L. Impact of CFTR DeltaF508 mutation on prostaglandin E2 production and type IIA phospholipase A2 expression by pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 289 (2005) L816-L824
Lemnaouar M., Chastre E., Paul A., Mergey M., Veissiere D., Cherqui G., et al. Oncogene-mediated propagation of tracheal epithelial cells from two cystic fibrosis fetuses with different mutations, characterization of CFT-1 and CFT-2 cells in culture. Eur J Clin Invest 23 (1993) 151-160
Jungas T., Motta I., Duffieux F., Fanen P., Stoven V., and Ojcius D.M. Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator. J Biol Chem 277 (2002) 27912-27918
Gruenert D.C., Basbaum C.B., Welsh M.J., Li M., Finkbeiner W.E., and Nadel J.A. Characterization of human tracheal epithelial cells transformed by an origin-defective simian virus 40. Proc Natl Acad Sci USA 85 (1988) 5951-5955
Kube D., Sontich U., Fletcher D., and Davis P.B. Proinflammatory cytokine responses to P. aeruginosa infection in human airway epithelial cell lines. Am J Physiol Lung Cell Mol Physiol 280 (2001) L493-L502
Bureau F., Bonizzi G., Kirschvink N., Delhalle S., Desmecht D., Merville M.P., et al. Correlation between nuclear factor-kappaB activity in bronchial brushing samples and lung dysfunction in an animal model of asthma. Am J Respir Crit Care Med 161 (2000) 1314-1321
Clifton D.R., Rydkina E., Freeman R.S., and Sahni S.K. NF-kappaB activation during Rickettsia rickettsii infection of endothelial cells involves the activation of catalytic IkappaB kinases IKKalpha and IKKbeta and phosphorylation-proteolysis of the inhibitor protein IkappaBalpha. Infect Immun 73 (2005) 155-165
Chariot A., Leonardi A., Muller J., Bonif M., Brown K., and Siebenlist U. Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases. J Biol Chem 277 (2002) 37029-37036
Mauro C., Vito P., Mellone S., Pacifico F., Chariot A., Formisano S., et al. Role of the adaptor protein CIKS in the activation of the IKK complex. Biochem Biophys Res Commun 309 (2003) 84-90
Heid C.A., Stevens J., Livak K.J., and Williams P.M. Real time quantitative PCR. Genome Res 6 (1996) 986-994
Giuliani C., Napolitano G., Bucci I., Montani V., and Monaco F. Nf-kB transcription factor: role in the pathogenesis of inflammatory, autoimmune, and neoplastic diseases and therapy implications. Clin Ter 152 (2001) 249-253
Viatour P., Merville M.P., and Bours VChariot A. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci 30 (2005) 43-52
Li Q., and Verma I.M. NF-kappaB regulation in the immune system. Nat Rev Immunol 2 (2002) 725-734
Hayden M.S., and Ghosh S. Signaling to NF-kappaB. Genes Dev 18 (2004) 2195-2224
Desmet C., Gosset P., Henry E., Garze V., Faisca P., Vos N., et al. Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1. Am J Respir Crit Care Med 172 (2005) 671-678
Holzberg D., Knight C.G., Dittrich-Breiholz O., Schneider H., Dorrie A., Hoffmann E., et al. Disruption of the c-JUN-JNK complex by a cell-permeable peptide containing the c-JUN delta domain induces apoptosis and affects a distinct set of interleukin-1-induced inflammatory genes. J Biol Chem 278 (2003) 40213-40223
Karin M., and Hunter T. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus. Curr Biol 5 (1995) 747-757
Cheng S.H., Gregory R.J., Marshall J., Paul S., Souza D.W., White G.A., et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63 (1990) 827-834
Ward C.L., and Kopito R.R. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins. J Biol Chem 269 (1994) 25710-25718
Dennis Jr. G., Sherman B.T., Hosack D.A., Yang J., Gao W., Lane H.C., et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4 (2003) P3
Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270 (1995) 16483-16486
Tabary O, Boncoeur E, de Martin R, Pepperkok R, Clement A, Schultz C, et al. Calcium-dependent regulation of NF-(kappa)B activation in cystic fibrosis airway epithelial cells. Cell Signal; 2005.
Weber A.J., Soong G., Bryan R., Saba S., and Prince A. Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function. Am J Physiol Lung Cell Mol Physiol 281 (2001) L71-L78
Cigana C., Nicolis E., Pasetto M., Assael B.M., and Melotti P. Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells. Biochem Biophys Res Commun 350 (2006) 977-982
Fu Z., Bettega K., Carroll S., Buchholz K.R., and Machen T.E. Role of Ca2+ in responses of airway epithelia to Pseudomonas aeruginosa, flagellin, ATP, and thapsigargin. Am J Physiol Lung Cell Mol Physiol 292 (2007) L353-L364
Chan M.M., Chmura K., and Chan E.D. Increased NaCl-induced interleukin-8 production by human bronchial epithelial cells is enhanced by the DeltaF508/W1282X mutation of the cystic fibrosis transmembrane conductance regulator gene. Cytokine 33 (2006) 309-316
Tchilibon S., Zhang J., Yang Q., Eidelman O., Kim H., Caohuy H., et al. Amphiphilic pyridinium salts block TNF alpha/NF kappa B signaling and constitutive hypersecretion of interleukin-8 (IL-8) from cystic fibrosis lung epithelial cells. Biochem Pharmacol 70 (2005) 381-393
Delgado M.A., Poschet J.F., and Deretic V. Nonclassical pathway of Pseudomonas aeruginosa DNA-induced interleukin-8 secretion in cystic fibrosis airway epithelial cells. Infect Immun 74 (2006) 2975-2984
Chun K.S., Keum Y.S., Han S.S., Song Y.S., Kim S.H., and Surh Y.J. Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-kappaB activation. Carcinogenesis 24 (2003) 1515-1524
Dhawan P., and Richmond A. A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells. J Biol Chem 277 (2002) 7920-7928
Kefaloyianni E., Gaitanaki C., and Beis I. ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-kappaB transactivation during oxidative stress in skeletal myoblasts. Cell Signal 18 (2006) 2238-2251
Vermeulen L., De Wilde G., Van Damme P., Vanden Berghe W., and Haegeman G. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 22 (2003) 1313-1324
Fan Z., Bau B., Yang H., and Aigner T. IL-1beta induction of IL-6 and LIF in normal articular human chondrocytes involves the ERK, p38 and NFkappaB signaling pathways. Cytokine 28 (2004) 17-24
Kida Y., Kobayashi M., Suzuki T., Takeshita A., Okamatsu Y., Hanazawa S., et al. Interleukin-1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase-1 production via activation of MAPK/AP-1 and NF-kappaB in human gingival fibroblasts. Cytokine 29 (2005) 159-168
Petrovic N., Knight D.A., Bomalaski J.S., Thompson P.J., and Misso N.L. Concomitant activation of extracellular signal-regulated kinase and induction of COX-2 stimulates maximum prostaglandin E2 synthesis in human airway epithelial cells. Prostaglandins Other Lipid Mediat 81 (2006) 126-135
Blau H, Klein K, Shalit I, Halperin D, Fabian I. Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK 1/2, JNK and NF-{kappa}B activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol; 2006.
Nanua S., Sajjan U., Keshavjee S., and Hershenson M.B. Absence of typical unfolded protein response in primary cultured cystic fibrosis airway epithelial cells. Biochem Biophys Res Commun 343 (2006) 135-143
Ribeiro C.M., Paradiso A.M., Schwab U., Perez-Vilar J., Jones L., O'Neal W., et al. Chronic airway infection/inflammation induces a Ca2+i-dependent hyperinflammatory response in human cystic fibrosis airway epithelia. J Biol Chem 280 (2005) 17798-17806
Zhou X., Yang W., and Li J. Ca2+- and protein kinase C-dependent signaling pathway for nuclear factor-kappaB activation, inducible nitric-oxide synthase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages. J Biol Chem 281 (2006) 31337-31347
Hu Q., Deshpande S., Irani K., and Ziegelstein R.C. [Ca(2+)](i) oscillation frequency regulates agonist-stimulated NF-kappaB transcriptional activity. J Biol Chem 274 (1999) 33995-33998
Quinlan K.L., Naik S.M., Cannon G., Armstrong C.A., Bunnett N.W., Ansel J.C., et al. Substance P activates coincident NF-AT- and NF-kappa B-dependent adhesion molecule gene expression in microvascular endothelial cells through intracellular calcium mobilization. J Immunol 163 (1999) 5656-5665
Han B., and Logsdon C.D. CCK stimulates mob-1 expression and NF-kappaB activation via protein kinase C and intracellular Ca(2+). Am J Physiol Cell Physiol 278 (2000) C344-C351
Pier G.B., Grout M., and Zaidi T.S. Cystic fibrosis transmembrane conductance regulator is an epithelial cell receptor for clearance of Pseudomonas aeruginosa from the lung. Proc Natl Acad Sci USA 94 (1997) 12088-12093
Guggino W.B. The cystic fibrosis transmembrane regulator forms macromolecular complexes with PDZ domain scaffold proteins. Proc Am Thorac Soc 1 (2004) 28-32
Yoo D., Flagg T.P., Olsen O., Raghuram V., Foskett J.K., and Welling P.A. Assembly and trafficking of a multiprotein ROMK (Kir 1.1) channel complex by PDZ interactions. J Biol Chem 279 (2004) 6863-6873
Wang X., Venable J., LaPointe P., Hutt D.M., Koulov A.V., Coppinger J., et al. Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127 (2006) 803-815
DiMango E., Ratner A.J., Bryan R., Tabibi S., and Prince A. Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells. J Clin Invest 101 (1998) 2598-2605
Gilmore T.D., and Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 25 (2006) 6887-6899
Olivier S., Robe P., and Bours V. Can NF-kappaB be a target for novel and efficient anti-cancer agents?. Biochem Pharmacol 72 (2006) 1054-1068
Lipecka J., Norez C., Bensalem N., Baudouin-Legros M., Planelles G., Becq F., et al. Rescue of DeltaF508-CFTR (cystic fibrosis transmembrane conductance regulator) by curcumin: involvement of the keratin 18 network. J Pharmacol Exp Ther 317 (2006) 500-505
Berger A.L., Randak C.O., Ostedgaard L.S., Karp P.H., Vermeer D.W., and Welsh M.J. Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl- channel activity. J Biol Chem 280 (2005) 5221-5226