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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:665757 |
| Date | January 2015 |
| Creators | Cunliffe, Helen Elizabeth |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/6129/ |
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