Tristetraprolin (TTP) coordinately regulates primary and secondary cellular responses to proinflammatory stimuli

J Leukoc Biol. 2015 Apr;97(4):723-36. doi: 10.1189/jlb.3A0214-106R. Epub 2015 Feb 5.


TTP is an anti-inflammatory protein that acts by binding to AREs in its target mRNAs, such as Tnf mRNA, and promoting their deadenylation and decay. TNF released from inflammatory cells can then stimulate gene expression in tissue cells, such as fibroblasts. To determine whether TTP could affect the decay of TNF-induced transcripts in fibroblasts, we exposed primary embryonic fibroblasts and stable fibroblast cell lines, derived from WT and TTP KO mice, to TNF. The decay rates of transcripts encoded by several early-response genes, including Cxcl1, Cxcl2, Ier3, Ptgs2, and Lif, were significantly slowed in TTP-deficient fibroblasts after TNF stimulation. These changes were associated with TTP-dependent increases in CXCL1, CXCL2, and IER3 protein levels. The TTP-susceptible transcripts contained multiple, conserved, closely spaced, potential TTP binding sites in their 3'-UTRs. WT TTP, but not a nonbinding TTP zinc finger mutant, bound to RNA probes that were based on the mRNA sequences of Cxcl1, Cxcl2, Ptgs2, and Lif. TTP-promoted decay of transcripts encoding chemokines and other proinflammatory mediators is thus a critical post-transcriptional regulatory mechanism in the response of secondary cells, such as fibroblasts, to TNF released from primary immune cells.

Keywords: AU-rich elements; mRNA decay; mouse embryonic fibroblasts; tumor necrosis factor.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 3' Untranslated Regions / genetics
  • AU Rich Elements
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Chemokine CXCL1 / biosynthesis
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL2 / biosynthesis
  • Chemokine CXCL2 / genetics
  • Chemotaxis, Leukocyte / physiology
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / genetics
  • Fibroblasts / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Humans
  • Immediate-Early Proteins / biosynthesis
  • Immediate-Early Proteins / genetics
  • Inflammation / physiopathology*
  • Leukemia Inhibitory Factor / biosynthesis
  • Leukemia Inhibitory Factor / genetics
  • Lipopolysaccharides / pharmacology
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA Stability / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Recombinant Fusion Proteins / metabolism
  • Toll-Like Receptors / agonists
  • Transcription, Genetic
  • Tristetraprolin / deficiency
  • Tristetraprolin / genetics
  • Tristetraprolin / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology


  • 3' Untranslated Regions
  • Chemokine CXCL1
  • Chemokine CXCL2
  • Cxcl1 protein, mouse
  • Cxcl2 protein, mouse
  • IEX-1 protein, mouse
  • Immediate-Early Proteins
  • Leukemia Inhibitory Factor
  • Lif protein, mouse
  • Lipopolysaccharides
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Toll-Like Receptors
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha
  • Zfp36 protein, mouse
  • lipopolysaccharide, E coli O55-B5
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2