Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2010) 21 S4.3

Imperial College London, London, UK.


Glucocorticoids (GCs) are used to treat inflammatory diseases because they downregulate expression of numerous inflammatory mediators. This is at least partly achieved through functional interference of the glucocorticoid receptor (GR) with transcription factors such as NF-κB (transrepression). On the other hand, activation of transcription by GR is responsible for some of the side effects of GCs. Efforts to improve the safety profile of GCs are focused on the identification of compounds that mediate transrepression whilst poorly activating gene expression. Such compounds (selective GR modulators or SGRMs) are predicted to retain anti-inflammatory effects but have fewer side effects.

However, GCs can also upregulate several anti-inflammatory mediators. For example, expression of the dual specificity phosphatase DUSP1 is increased by GCs in many cell types. DUSP1 dephosphorylates and inactivates mitogen-activated protein kinases (MAPKs) that are required for expression of pro-inflammatory gene products. Hence the induction of DUSP1 is a mechanism for restraining inflammatory responses, and DUSP1−/− mouse macrophages are partially insensitive to anti-inflammatory effects of GCs.

GC regulation of DUSP1 gene expression is unusual. Several consensus GR binding sites are conserved between mouse and human DUSP1 loci up to 29 kb upstream of the transcription start site, but these sites are differentially employed by the two organisms. The mouse DUSP1 gene is regulated via an element at −29 kb, the human DUSP1 gene via elements at −4.6 and −1.3 kb. Unusually, transcriptional induction is independent of GR dimerisation in both species. Induction of DUSP1 by GC is highly sensitive to cell density, whereas other GC responses are unaffected by cell density. Perhaps reflecting the unusual control of the DUSP1 gene, it can be induced by two recently described SGRMs. We discuss the possibility that both conventional GCs and SGRMs exert anti-inflammatory effects both by transrepression and by upregulation of anti-inflammatory mediators like DUSP1.

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