Transcriptional regulation of the anti-inflammatory protein tristetraprolin (TTP)

[摘要] Feedback node genes (FNGs) are essential for negative feedback control of inflammatory responses. By definition, their expression is controlled by both pro- and anti-inflammatory stimuli, often in a cooperative manner. This thesis investigates three FNGs, namely Dual specificity phosphatase 1 (DUSP1), Tumour necrosis factor alpha inducible protein 3 (TNFAIP3) and Tristetraprolin (TTP, encoded by the \(Zfp36\) gene). DUSP1 is a negative feedback regulator of mitogen-activated protein kinases, TNFAIP3 negatively regulates the nuclear factor κB (NF-κB) signalling pathway and TTP is a destabiliser of pro-inflammatory mRNAs. All three FNGs were induced by pro-inflammatory stimuli, with very different dependence on NF-κB signalling. Further to this, the anti-inflammatory agonists dexamethasone, prostaglandin E\(_2\) (PGE\(_2\)) and transforming growth factor β (TGFβ) were able to impair NF-κB activity and yet cooperated with pro-inflammatory agonists to increase expression of all three FNGs. Experiments in primary mouse knock-out macrophages suggested that DUSP1 may be necessary for some anti-inflammatory effects of PGE\(_2\), and for the cooperative regulation of other FNGs by pro- and anti-inflammatory agonists. Three putative regulatory elements located upstream of the \(Zfp36\) locus were shown to mediate cooperative transcriptional regulation by various combinations of pro- and anti-inflammatory agonists. Chromatin immunoprecipitation experiments also demonstrated dynamic remodelling of the locus in response to a pro-inflammatory stimulus.

[发布机构] University:University of Birmingham;Department:School of Immunity and Infection

[关键词] Q Science;QH Natural history;QH426 Genetics