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 :

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 :

FNRS, TELEVIE, PAI

Available on ORBi :

since 06 January 2009

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