060 - Pro-inflammatory effect of sodium 4-phenylbutyrate in ΔF508-CFTR lung cells: Involvement of ERK1/2 and JNK signaling - 05/12/08

Sodium 4-phenylbutyrate (4-PBA) has attracted a great deal of attention in cystic fibrosis (CF) pathology due to its capacity to traffic ΔF508-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 (used within a therapeutically relevant range, 6 to 10 mM for 24h) 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-ΔB transcriptional activities in the two ΔF508-CFTR lung cells either in a resting state or after TNF-Δ 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 ΔF508-CFTR lung cell lines treated with 4-PBA. In CFBE41o- and IB3-1 cells treated with 4-PBA, we observed a significant increase of the ΔF508-CFTR protein in cell membrane. After 8 mM 4-PBA treatment, the increase of apical membrane ΔF508-CFTR protein in CFBE41o- and IB3-1 cells was 2.5- and 8.0-fold compared to untreated control cells, respectively. No significant change of the amount of apical membrane ΔF508- CFTR protein was observed following an inhibition of both ERK1/ 2 and JNK signaling in two 4-PBA-treated CFBE41o- and IB3-1 cells.

We thus propose that targeting both the ERK1/2 and JNK pathway with selective molecule kinase inhibitors for reducing damaging lung inflammation, in combination with a treatment with 4-PBA to improve CFTR chloride function in CF lung epithelium, is certainly a promising therapeutic strategy for cystic fibrosis (Roque T et coll., JPET, 2008, in press).

Supported by the French Cystic Fibrosis association (Vaincre La Mucoviscidose).