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Keratinocyte Growth Factor Expression by Fibroblasts in Pulmonary Fibrosis

Poor Response to Interleukin-1ß

INSERM unit 408 and INSERM unit 327, Faculté Xavier Bichat, Université Paris 7; Service de Pneumologie, and Laboratoire de Biochimie A, Hôpital Bichat; and Service de Chirurgie Thoracique et Vasculaire, and Service de Pneumologie, Hôpital Beaujon, Clichy, Assistance Publique-Hôpitaux de Paris, Paris, France

Correspondence and requests for reprints should be addressed to Dr. Bruno Crestani, Service de Pneumologie, Hôpital Bichat, 16 rue Henri Huchard, 75877, Paris cedex 18, France. E-mail: bruno.crestani{at}bch.ap-hop-paris.fr

Keratinocyte growth factor (KGF) is secreted by fibroblasts and protects from pulmonary fibrosis in animal models. Interleukin (IL)-1ß 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-1ß stimulation. Basal KGF secretion by IPF fibroblasts was similar to controls. In fibroblasts from control subjects, IL-1ß 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-1ß. By contrast, in IPF fibroblasts, IL-1ß did not increase c-Jun expression and c-Jun activation, and weakly increased KGF secretion, whereas SP600125 had no effect. IL-1ß similarly increased JunB expression in fibroblasts from patients with IPF and control subjects. Total JNK content was not different in either unstimulated or IL-1ß–stimulated IPF and control fibroblasts. IL-1ß 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-1ß is associated with a defect of c-Jun expression and activation and a defect of JNK activation.

Key Words: human • lung • MAP kinase • transcription factors • usual interstitial pneumonia

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