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Am J Physiol Lung Cell Mol Physiol 296: L1012-L1018, 2009. First published April 10, 2009; doi:10.1152/ajplung.90601.2008
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Tristetraprolin regulates IL-8 mRNA stability in cystic fibrosis lung epithelial cells

Nagaraja Sethuraman Balakathiresan,1 Sharmistha Bhattacharyya,1 Usha Gutti,1 Robert P. Long,1 Catherine Jozwik,2 Wei Huang,2 Meera Srivastava,2 Harvey B. Pollard,2 and Roopa Biswas1

Departments of 1Health Systems, Risk, and Contingency Management, Graduate School of Nursing, and 2Anatomy, Physiology, and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Submitted 4 December 2008 ; accepted in final form 8 April 2009

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.

cytokines; chemokines; inflammation; gene regulation


Address for reprint requests and other correspondence: R. Biswas, Graduate School of Nursing, Rm. B4024, Uniformed Services Univ. of the Health Sciences, Bethesda, MD 20814 (e-mail: rbiswas{at}usuhs.mil)






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