Dataset Information

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.

SUBMITTER: Qiu LQ

PROVIDER: S-EPMC4370050 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Qiu Lian-Qun LQ Lai Wi S WS Bradbury Alyce A Zeldin Darryl C DC Blackshear Perry J PJ

Journal of leukocyte biology 20150205 4

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 enc ...[more]

PMID: 25657290

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Project description:Alzheimer's disease (AD) is a heterogeneous degenerative disorder of the brain that is on the rise worldwide. One of the critical processes that might be disturbed in AD is gene expression regulation. Tristetraprolin (TTP) and RC3H1 gene (ROQUIN) are two RNA-binding proteins (RBPs) that target AU-rich elements (AREs) and constitutive decay elements (CDEs), respectively. TTP and ROQUIN, members of the CCCH zinc-finger protein family, have been demonstrated to fine-tune numerous inflammatory factors. In addition, miR-16 has distinct characteristics and may influence the target mRNA through the ARE site. Interestingly, BDNF mRNA has ARE sites in the 3' untranslated region (UTR) and can be targeted by regulatory factors, such as TTP and miR-16 on MRE sequences, forming BDNF/miR-16/TTP regulatory axis. A number of two microarray datasets were downloaded, including information on mRNAs (GSE106241) and miRNAs (GSE157239) from individuals with AD and corresponding controls. R software was used to identify BDNF, TTP, ROQUIN, and miR-16 expression levels in temporal cortex (TC) tissue datasets. Q-PCR was also used to evaluate the expression of these regulatory factors and the expression of BDNF in the blood of 50 patients with AD and 50 controls. Bioinformatic evaluation showed that TTP and miR-16 overexpression might act as post-transcriptional regulatory factors to control BDNF expression in AD in TC samples. Instead, this expression pattern was not found in peripheral blood samples from patients with AD compared to normal controls. ROQUIN expression was increased in the peripheral blood of patients with AD. Hsa-miR-16-5p levels did not show significant differences in peripheral blood samples. Finally, it was shown that TTP and BDNF, based on evaluating the receiver operating characteristic (ROC), effectively identify patients with AD from healthy controls. This study could provide a new perspective on the molecular regulatory processes associated with AD pathogenic mechanisms linked to the BDNF growth factor, although further research is needed on the possible roles of these factors in AD.

Dataset Information

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

Publications

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

Similar Datasets

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