title: Tristetraprolin (TTP) coordinately regulates primary and secondary cellular responses to proinflammatory stimuli.
abstract: 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.
authors: *Laboratories of Signal Transduction and Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; and Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
authors: Lian-Qun
authors: LQ
authors: Qiu
authors: *Laboratories of Signal Transduction and Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; and Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
authors: Wi S
authors: WS
authors: Lai
authors: *Laboratories of Signal Transduction and Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; and Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
authors: Alyce
authors: A
authors: Bradbury
authors: *Laboratories of Signal Transduction and Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; and Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
authors: Darryl C
authors: DC
authors: Zeldin
authors: *Laboratories of Signal Transduction and Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; and Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina, USA black009@niehs.nih.gov.
authors: Perry J
authors: PJ
authors: Blackshear
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D063307:AU Rich Elements; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000096:biosynthesis / Q000235:genetics; D054426:Chemokine CXCL2 / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000503:physiopathology*; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists; D014158:Transcription, Genetic; D051816:Tristetraprolin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D051193:Toll-Like Receptors; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; C482199:lipopolysaccharide, E coli O55-B5; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: AU-rich elements; mRNA decay; mouse embryonic fibroblasts; tumor necrosis factor
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