Expression of the CFTR (cystic fibrosis transmembrane conductance regulator) gene which mutations are responsible for cystic fibrosis, is regulated by cytokines (TNF and IL-1) in a cell specific-manner: TNF decreases CFTR mRNA in human colon cell lines (HT-29) but not in pulmonary cell lines (Calu-3), IL-1 increases it only in Calu-3 cells. We have looked for the cytokines-induced posttranscriptional regulation of CFTR gene expression and studied the modulation of CFTR mRNA stability linked to its 3'untranslated sequence (3'UTR) in HT-29 and Calu-3 cells. The stability of CFTR mRNA was analyzed by Northernblot after in vitro incubation of total RNAs from CFTR-expressing cells with cytosolic proteins extracted from control or cytokine-treated HT-29 and Calu-3 cells. CFTR mRNA was degraded only by extracts of TNF-treated HT-29 cells and not by cytosolic proteins from untreated or IL-1-treated HT-29 cells. In contrast, extracts of untreated Calu-3 cells enhanced CFTR mRNA degradation, and IL-1 treatment inhibited this; TNF had no significant effect. The 3'UTR part of CFTR mRNA was found to be required for this posttranscriptional regulation. The 5' part of the 3'UTR (the 250 first bases), which contains two AUUUA sequences, was implicated in CFTR mRNA destabilization and the following 140 bases, containing several C-repeats in U-rich environment, in its protection. The proteins which reacted with the U- and C-repeats of CFTR mRNA 3'UTR were mainly controlled by stimulation of the p42/p44 and p38 MAP kinase cascades with interaction between these pathways. This posttranscriptional control of gene expression is a common feature of CFTR and many proteins of inflammation.