Abstract
Glucocorticoids (corticosteroids) are highly effective in combating inflammation in the context of a variety of diseases. However, clinical utility can be compromised by the development of side effects, many of which are attributed to the ability of the glucocorticoid receptor (GR) to induce the transcription of, or transactivate, certain genes. By contrast, the anti-inflammatory effects of glucocorticoids are due largely to their ability to reduce the expression of pro-inflammatory genes. This effect has been predominantly attributed to the repression of key inflammatory transcription factors, including AP-1 and NF-κB, and is termed transrepression. The ability to functionally separate these transcriptional functions of GR has prompted a search for dissociated GR ligands that can differentially induce transrepression but not transactivation. In this review, we present evidence that post-transcriptional mechanisms of action are highly important to the anti-inflammatory actions of glucocorticoids. Furthermore, we present the case that mechanistically distinct forms of glucocorticoid-inducible gene expression are critical to the development of anti-inflammatory effects by repressing inflammatory signaling pathways and inflammatory gene expression at multiple levels. Considerable care is therefore required to avoid loss of anti-inflammatory effectiveness in the development of novel transactivation-defective ligands of GR.
Footnotes
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R.N. is a Canadian Institutes of Health Research (CIHR) New Investigator and Alberta Heritage Foundation for Medical Research (AHFMR) Scholar. Work in the laboratory of R.N. is supported by CIHR and AHFMR as well as by research awards from AstraZenenca, Altana, and GlaxoSmithKline.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.038794.
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ABBREVIATIONS: GR, glucocorticoid receptor; GRE, glucocorticoid response element; TAT, tyrosine amino transferase; IL, interleukin; POMC, pro-opiomelanocortin; nGRE, negative GRE site; AP-1, activator protein-1; ATF, activating transcription factor; C/EBP, CCAAT/enhancer binding protein; NF-κB, nuclear factor-κB; IκB, inhibitor of κB; CBP, cAMP response element-binding protein binding protein; RU24858; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; MKP-1, mitogen-activated protein kinase phosphatase; ARE, AU-rich element; JNK, c-Jun N-terminal kinase; GILZ, glucocorticoid-inducible leucine zipper; Dok, downstream of tyrosine kinase; Pol, RNA polymerase; SRC, steroid receptor coactivator.
- Received June 5, 2007.
- Accepted July 10, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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