Oxidative stress induces extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase in cystic fibrosis lung epithelial cells: Potential mechanism for excessive IL-8 expression.
Cystic fibrosis (CF) is a lethal disease caused by defective function of the cftr gene product, the CF transmembrane conductance regulator (CFTR) that leads to oxidative damage and excessive inflammatory response in lungs of CF patients. We here report the effects of oxidative stress (hyperoxia, 95% O(2)) on the expression of pro-inflammatory interleukin (IL)-8 and CXCR1/2 receptors in two human CF lung epithelial cell lines (IB3-1, with the heterozygous F508del/W1282X mutation and CFBE41o- with the homozygous F508del/F508del mutation) and two control non-CF lung epithelial cell lines (S9 cell line derived from IB3-1 after correction with wtCFTR and the normal bronchial cell line 16HBE14o-). Under oxidative stress, the expression of IL-8 and CXCR1/2 receptors was increased in CF, corrected and normal lung cell lines. The effects of oxidative stress were also investigated by measuring the transcription nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) activities. Under oxidative stress, no increase of NF-kappaB activation was observed in CF lung cells in contrast to that observed in normal and corrected CF lung cells. The signalling of mitogen-activated protein (MAP) kinases was further studied. We demonstrated that extracellular signal-regulated kinase (ERK1/2) and AP-1 activity was markedly enhanced in CF but not non-CF lung cells under oxidative stress. Consistently, inhibition of ERK1/2 in oxidative stress-exposed CF lung cells strongly decreased both the IL-8 production and CXCR1/2 expression. Therefore, targeting of ERK1/2 MAP kinase may be critical to reduce oxidative stress-mediated inflammation in lungs of CF patients.
Boncoeur
Emilie
E
Inserm, U719, Paris F-75012, France.
Criq
Vinciane Saint
VS
Bonvin
Elise
E
Roque
Telma
T
Henrion-Caude
Alexandra
A
Gruenert
Dieter C
DC
Clement
Annick
A
Jacquot
Jacky
J
Tabary
Olivier
O
D002460:Cell Line; D003550:Cystic Fibrosis / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008168:Lung / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D054387:Receptors, CXCR / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D048049:Extracellular Signal-Regulated MAP Kinases; D016209:Interleukin-8; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D054387:Receptors, CXCR; D018808:Transcription Factor AP-1; D000097782:NF-kappaB-Inducing Kinase