Dual specificity phosphatase 1 (DUSP1): an important regulator of the anti-inflammatory actions of glucocorticoids?

The Mitogen Activated Protein Kinases (MAPKs) are a family of serine/threonine kinases that orchestrate changes in gene expression in response to extracellular stimuli. The c-Jun N-terminal kinase (JNK) and p38 MAPK subfamilies are strongly activated by pro-inflammatory stimuli such as UV light, cytokines such as Interleukin-l (IL-I), and pathogen-associated molecules, for example lipopolysaccharide (LPS). The JNK and p38 signalling pathways control the expression of many inflammatory mediators, including tumour necrosis factor a (lNFa) and cyclooxygenase 2 (COX-2). Activation of MAPKs requires their phosphorylation at particular threonine and tyrosine residues. Conversely, inactivation of the MAPKs is achieved by removal of the activating phosphate groups by various threonine / serine-, tyrosine-, or dual specificity phosphatases. This phosphatase-mediated inactivation ofp38 and JNK is thought to be critical for limiting the strength and duration ofan inflammatory response.We and others have shown that the dual-specificity phosphatase, DUSPI is transiently upregulated by proinflammatory stimuli such as UV light, IL-I or LPS. It is also upregulated in a more sustained fashion by the glucocorticoid dexamethasone, a powerful anti-inflammatory agonist. The induction of DUSPI gene expression coincides with the inactivation of JNK and p38. We hypothesised that DUSPI plays a role in the limitation of inflammatory responses via a negative feedback loop, and that the sustained induction of DUSPI contributes to the anti-inflammatory effects ofglucocorticoids. To test these hypotheses we have investigated inflammatory responses of cells from a DUSPI knock-out mouse.EThOS - Electronic Theses Online ServiceGBUnited Kingdo