The role of microRNAs in glucocorticoid action

Abstract

Glucocorticoids (GCs) are steroids with profound anti-inflammatory and immunomodulatory activities. Synthetic GCs are widely used for managing chronic inflammatory and autoimmune conditions, as immunosuppressants in transplantation, and as anti-tumor agents in certain hematological cancers. However, prolonged GC exposure can cause adverse effects. A detailed understanding of GCs' mechanisms of action may enable harnessing of their desirable actions while minimizing harmful effects. Here, we review the impact on the GC biology of microRNAs, small non-coding RNAs that post-transcriptionally regulate gene expression. Emerging evidence indicates that microRNAs modulate GC production by the adrenal glands and the cells' responses to GCs. Furthermore, GCs influence cell proliferation, survival, and function at least in part by regulating microRNA expression. We propose that the beneficial effects of GCs may be enhanced through combination with reagents targeting specific microRNAs.

Keywords: apoptosis; epigenetics; glucocorticoid; glucocorticoid receptor; inflammation; microRNA (miRNA).

Figure 1.

Regulation of GC biosynthesis by miRNAs. The endogenous human glucocorticoid cortisol and the mineralocorticoid aldosterone are synthesized in the adrenal cortex from cholesterol. miRNAs have been reported to regulate this synthesis by the targeting of cytochrome p450 enzymes.

Figure 2.

miRNA biogenesis and function. miRNAs are transcribed from the genome to create primary (pri-)miRNAs. The first round of cleavage occurs in the nucleus, carried out by the RNase III enzyme Drosha and associated factor Pasha/DGCR8, resulting in the shorter precursor (pre-)miRNA. Nuclear export is mediated by Exportin 5 (XPO5) and Ran-GTP. The second cleavage is carried out in the cytoplasm by the RNase III enzyme Dicer as part of a protein complex that produces the mature miRNA. Strand selection results in release of one of the two miRNA strands, which is degraded. The retained strand is loaded onto Argonaute protein (e.g. Ago2) and forms RISC along with other proteins such as GW182. Silencing can occur by promoting deadenylation and mRNA degradation or translational repression.

Figure 3.

Impact of miRNAs on GC biology. miRNAs modulate every aspect of GC biology, including the biosynthesis of GCs in the adrenal cortex, the localized conversion of cortisone to cortisol, the expression of the GC receptor, and its ability to respond to GC. Expression of miRNAs is also positively or negatively regulated by GCs as a means of bringing about changes in cell proliferation, survival, and function.