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Effects of spironolactone on human blood mononuclear cells: mineralocorticoid receptor independent effects on gene expression and late apoptosis induction
Article first published online: 29 JAN 2009
DOI: 10.1038/sj.bjp.0706700
2006 British Pharmacological Society
1476-5381/asset/cover.gif?v=1&s=f56f5a76559ff1cebf2b6e329fe028f1e9e0f463 "British Journal of Pharmacology")
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How to Cite
Sønder, S. U. S., Mikkelsen, M., Rieneck, K., Hedegaard, C. J. and Bendtzen, K. (2006), Effects of spironolactone on human blood mononuclear cells: mineralocorticoid receptor independent effects on gene expression and late apoptosis induction. British Journal of Pharmacology, 148: 46–53. doi: 10.1038/sj.bjp.0706700
Publication History
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received November 11, 2005, Accepted January 20, 2006)
- Abstract
- Article
- References
- Cited By
Keywords:
- Mineralocorticoid receptors;
- immunotherapy;
- inflammation;
- pharmacology;
- gene expression;
- autoimmunity;
- cytokines;
- programmed cell death
- 1Spironolactone (SPIR) binds to cytoplasmic mineralocorticoid receptors (MR) and functions as an aldosterone antagonist. Recently, the drug was shown to have an early suppressive effect on several immunoactive and proinflammatory cytokines.
- 2To elucidate the mechanism behind this, the four MR-binding steroids SPIR, canrenone, 7α-thiomethyl-spironolactone and aldosterone (ALDO) were investigated for effects on lipopolysaccharide- and phytohemagglutinin-A-activated human blood mononuclear cells. Gene expression was examined after 4 h using microarrays, and SPIR affected 1018 transcripts of the (=) 22,000 probed. In contrast, the SPIR-related steroids affected 17 or fewer transcripts. Combining SPIR and ALDO resulted in 940 affected transcripts, indicating that SPIR has an early gene-regulatory effect independent of MR.
- 3The affected genes encode a large number of signalling proteins and receptors, including immunoinflammatory response genes and apoptosis and antiapoptosis genes. Apoptosis was evident in CD3-, CD14- and CD19-positive cells, but only after 18 h of exposure to SPIR.
- 4The transcriptional network involving the differentially regulated genes was examined and the results indicate that SPIR affects genes controlled by the transcription factors NF-κB, CEBPβ and MYC.
- 5These observations provide new insight into the non-MR-mediated effects of SPIR.
British Journal of Pharmacology (2006) 148, 46–53. doi:10.1038/sj.bjp.0706700