Tristetraprolin regulates IL-8 mRNA stability in cystic fibrosis lung epithelial cells

Balakathiresan NS, Bhattacharyya S, Gutti U, Long RP, Jozwik C, Huang W, Srivastava M, Pollard HB, Biswas R. Tristetraprolin regulates IL-8 mRNA stability in cystic fibrosis lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 296: L1012-L1018, 2009. First published April 10, 2009; doi: 10.1152/ajplung.90601.2008.-Cystic fibrosis (CF) is due to mutations in the CFTR gene and is characterized by hypersecretion of the proinflammatory chemokine IL-8 into the airway lumen. Consequently, this induces the highly inflammatory cellular phenotype typical of CF. Our initial studies revealed that IL-8 mRNA is relatively stable in CF cells compared with those that had been repaired with [WT] CFTR (wild-type CFTR). Relevantly, the 3'-UTR of IL-8 mRNA contains AU-rich sequences (AREs) that have been shown to mediate posttranscriptional regulation of proinflammatory genes upon binding to ARE-binding proteins including Tristetraprolin (TTP). We therefore hypothesized that very low endogenous levels of TTP in CF cells might be responsible for the relative stability of IL-8 mRNA. As predicted, increased expression of TTP in CF cells resulted in reduced stability of IL-8 mRNA. An in vitro analysis of IL-8 mRNA stability in CF cells also revealed a TTP-induced enhancement of deadenylation causing reduction of IL-8 mRNA stability. We conclude that enhanced stability of IL-8 mRNA in TTP-deficient CF lung epithelial cells serve to drive the proinflammatory cellular phenotype in the CF lung.