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Tristetraprolin (TTP) coordinately regulates primary and secondary cellular
responses to proinflammatory stimuli
#MMPMID25657290
Qiu LQ
; Lai WS
; Bradbury A
; Zeldin DC
; Blackshear PJ
J Leukoc Biol
2015[Apr]; 97
(4
): 723-36
PMID25657290
show ga
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.
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