Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta.
Keratinocyte growth factor (KGF) is secreted by fibroblasts and protects from pulmonary fibrosis in animal models. Interleukin (IL)-1beta is the most potent inducer of KGF in fibroblasts, acting through the c-Jun pathway. We evaluated in vitro KGF production by human lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF, n = 10) and from control subjects (n = 7) at baseline and after IL-1beta stimulation. Basal KGF secretion by IPF fibroblasts was similar to controls. In fibroblasts from control subjects, IL-1beta increased c-Jun expression, c-Jun activation, and KGF secretion. SP600125, a specific c-Jun N-terminal kinase (JNK) inhibitor, inhibited the effect of IL-1beta. By contrast, in IPF fibroblasts, IL-1beta did not increase c-Jun expression and c-Jun activation, and weakly increased KGF secretion, whereas SP600125 had no effect. IL-1beta similarly increased JunB expression in fibroblasts from patients with IPF and control subjects. Total JNK content was not different in either unstimulated or IL-1beta-stimulated IPF and control fibroblasts. IL-1beta increased phosphorylated JNK in control and IPF fibroblasts, but this increase was weaker and heterogeneous in IPF. Altogether, our results demonstrate a dysregulation of KGF secretion by IPF fibroblasts. The weak response to IL-1beta is associated with a defect of c-Jun expression and activation and a defect of JNK activation.
Marchand-Adam
Sylvain
S
Service de Pneumologie, Hôpital Bichat, 16 rue Henri Huchard, 75877 Paris cedex 18, France.
Plantier
Laurent
L
Bernuau
Dominique
D
Legrand
Agnès
A
Cohen
Murielle
M
Marchal
Joëlle
J
Soler
Paul
P
Lesèche
Guy
G
Mal
Hervé
H
Aubier
Michel
M
Dehoux
Monique
M
Crestani
Bruno
B
D000328:Adult; D000368:Aged; D000818:Animals; D000873:Anthracenes / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008875:Middle Aged; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*
D000873:Anthracenes; C496453:FGF7 protein, human; D007375:Interleukin-1; D016755:Proto-Oncogene Proteins c-jun; D051523:Fibroblast Growth Factor 7; C432165:pyrazolanthrone; D005346:Fibroblast Growth Factors; D048031:JNK Mitogen-Activated Protein Kinases