Tristetraprolin regulates IL-8 mRNA stability in cystic fibrosis lung epithelial cells.
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.
Departments of Health Systems, Risk, and Contingency Management, Graduate School of Nursing, Uniformed Services Univ. of the Health Sciences, Bethesda, MD 20814, USA.
Nagaraja Sethuraman
NS
Balakathiresan
Sharmistha
S
Bhattacharyya
Usha
U
Gutti
Robert P
RP
Long
Catherine
C
Jozwik
Wei
W
Huang
Meera
M
Srivastava
Harvey B
HB
Pollard
Roopa
R
Biswas
D000225:Adenine / Q000378:metabolism; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics* / Q000503:physiopathology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D010641:Phenotype; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000502:physiology; D020545:Respiratory Mucosa / Q000166:cytology / Q000502:physiology*; D051816:Tristetraprolin / Q000378:metabolism*
D016209:Interleukin-8; D012333:RNA, Messenger; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D000225:Adenine