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

Autor: Wi S. Lai, Lian-Qun Qiu, Darryl C. Zeldin, Perry J. Blackshear, Alyce Bradbury
Rok vydání: 2015
Předmět:
Lipopolysaccharides
Transcription
Genetic
Chemokine CXCL1
RNA Stability
Recombinant Fusion Proteins
IER3
Chemokine CXCL2
Immunology
Tristetraprolin
Biology
Leukemia Inhibitory Factor
Immediate early protein
Immediate-Early Proteins
Proinflammatory cytokine
Mice
hemic and lymphatic diseases
Animals
Humans
Immunology and Allergy
heterocyclic compounds
RNA
Messenger
3' Untranslated Regions
neoplasms
Cells
Cultured
AU Rich Elements
Inflammation
Mice
Knockout
AU-rich element
Regulation of gene expression
Messenger RNA
Binding Sites
Tumor Necrosis Factor-alpha
Macrophages
Inflammation
Extracellular Mediators
& Effector Molecules
Toll-Like Receptors
Cell Biology
Fibroblasts
respiratory system
Molecular biology
Mice
Inbred C57BL
Chemotaxis
Leukocyte
Gene Expression Regulation
Cyclooxygenase 2
Tumor necrosis factor alpha
therapeutics
Zdroj: Journal of Leukocyte Biology. 97:723-736
ISSN: 1938-3673
0741-5400
Popis: 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.
Databáze: OpenAIRE
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