Received for publication December 20, 2007.
Revised June 20, 2008.
Accepted for publication June 20, 2008.

Pro-inflammatory effect of sodium 4-phenylbutyrate in F508-CFTR lung epithelial cells: Involvement of ERK1/2 and JNK signaling

Abstract

Sodium 4-phenylbutyrate (4-PBA) has attracted a great deal of attention in cystic fibrosis (CF) pathology due to its capacity to traffic F508-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 pro-inflammatory cytokine IL-8 production in a concentration-dependent manner. This 4-PBA-induced IL-8 production was associated with a strong reduction of proteasome and NF-B transcriptional activities in the two F508-CFTR lung cells either in a resting state or after TNF- stimulation. In contrast, a strong increase of AP-1 transcriptional activity was observed. The inhibition of ERK1/2 by U0126, PD98059 and JNK MAPK by SP600125 was respectively associated with a reduction (2- to 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 following an inhibition of p38 MAPK with SB202190. We therefore 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.

Key words: AP-1, Cystic fibrosis, ERK1/2, IL-8, Lung inflammation, NF-kB