title: Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta.
abstract: 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.
authors.affiliation: Service de Pneumologie, Hôpital Bichat, 16 rue Henri Huchard, 75877 Paris cedex 18, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Marchand-Adam
authors.forename: Laurent
authors.initials: L
authors.lastname: Plantier
authors.forename: Dominique
authors.initials: D
authors.lastname: Bernuau
authors.forename: Agnès
authors.initials: A
authors.lastname: Legrand
authors.forename: Murielle
authors.initials: M
authors.lastname: Cohen
authors.forename: Joëlle
authors.initials: J
authors.lastname: Marchal
authors.forename: Paul
authors.initials: P
authors.lastname: Soler
authors.forename: Guy
authors.initials: G
authors.lastname: Lesèche
authors.forename: Hervé
authors.initials: H
authors.lastname: Mal
authors.forename: Michel
authors.initials: M
authors.lastname: Aubier
authors.forename: Monique
authors.initials: M
authors.lastname: Dehoux
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
mesh_terms: 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*
chemical_list: 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