TY - JOUR T1 - Proinflammatory Effect of Sodium 4-Phenylbutyrate in ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Lung Epithelial Cells: Involvement of Extracellular Signal-Regulated Protein Kinase 1/2 and c-Jun-NH<sub>2</sub>-Terminal Kinase Signaling JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 949 LP - 956 DO - 10.1124/jpet.107.135186 VL - 326 IS - 3 AU - Telma Roque AU - Emilie Boncoeur AU - Vinciane Saint-Criq AU - Elise Bonvin AU - Annick Clement AU - Olivier Tabary AU - Jacky Jacquot Y1 - 2008/09/01 UR - http://jpet.aspetjournals.org/content/326/3/949.abstract N2 - Sodium 4-phenylbutyrate (4-PBA) has attracted a great deal of attention in cystic fibrosis (CF) pathology due to its capacity to traffic ΔF508-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 ΔF508-CFTR lung epithelial cell lines (CFBE41o- and IB3-1 cells, characterized with ΔF508-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-κB transcriptional activities in the two ΔF508-CFTR lung cells either in a resting state or after tumor necrosis factor-α 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 ΔF508-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. The American Society for Pharmacology and Experimental Therapeutics ER -