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CELLULAR AND MOLECULAR

Proinflammatory Effect of Sodium 4-Phenylbutyrate in F508-Cystic Fibrosis Transmembrane Conductance Regulator Lung Epithelial Cells: Involvement of Extracellular Signal-Regulated Protein Kinase 1/2 and c-Jun-NH₂-Terminal Kinase Signaling

Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 893, Paris, France (T.R., E.B., V.S.-C., E.B., A.C., O.T., J.J.); Université Pierre et Marie Curie, Université Paris 06, Paris, France (T.R., E.B., V.S.-C., E.B., A.C., O.T., J.J.); and Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Pediatric Pulmonary Department, Paris, France (A.C.)

Sodium 4-phenylbutyrate (4-PBA) has attracted a great deal of attention in cystic fibrosis (CF) pathology due to its capacity to traffic F508-cystic fibrosis transmembrane conductance regulator (CFTR) to the cell membrane and restore CFTR chloride function at the plasma membrane of CF lung cells in vitro and in vivo. Using two different F508-CFTR lung epithelial cell lines (CFBE41o- and IB3-1 cells, characterized with F508-homozygous and heterozygous genotype, respectively) in vitro, 4-PBA induced an increase of proinflammatory cytokine interleukin (IL)-8 production in a concentration-dependent manner. This 4-PBA-induced IL-8 production was associated with a strong reduction of proteasome and nuclear factor-B transcriptional activities in the two F508-CFTR lung cells either in a resting state or after tumor necrosis factor- stimulation. In contrast, a strong increase of activator protein-1 transcriptional activity was observed. The inhibition of extracellular signal-regulated protein kinase 1/2 (ERK1/2) by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126) and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) and c-Jun-NH₂-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) by anthra[1,9-cd] pyrazol-6 (2H)-one (SP600125), respectively, was associated with a reduction (2–3.5-fold) of IL-8 production in both F508-CFTR lung cell lines treated with 4-PBA. No significant change of IL-8 production was observed after an inhibition of p38 MAPK with 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] phenol (SB202190). Therefore, we suggest that inhibition of both ERK1/2 and JNK signaling may be a means to strongly reduce 4-PBA-induced IL-8 production in combination with 4-PBA treatment to restore CFTR Cl^- channel function in lung epithelial cells of patients with CF.

Address correspondence to: Dr. Jacky Jacquot, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 893, Hôpital Saint-Antoine, 184, rue du Fg Saint-Antoine, 75012 Paris, France. E-mail: jacky.jacquot{at}inserm.fr