miRNA regulation of cytokine genes

Abstract

In this review we discuss specific examples of regulation of cytokine genes and focus on a new mechanism involving post-transcriptional regulation via miRNAs. The post-transcriptional regulation of cytokine genes via the destabilizing activity of AU-rich elements [AREs] and miRNAs is a pre-requisite for regulating the half-life of many cytokines and achieving the temporal and spatial distributions required for regulation of these genes.

Fig. 1

A schematic representation of miRNA processing and activity. MicroRNAs are transcribed by RNA polymerase enzymes (mainly Pol III) as part of primary miRNA molecules. Two dsRNA-specific ribonucleases, Drosha and Dicer sequentially cleave the long-primary miRNA into the precursor hairpin miRNA and the mature miRNA (22 nt), respectively. A single strand of this mature miRNA enters the RNA-induced silencing complex (RISC) that mediates the miRNA function.

Fig. 2

miRNA and transcription factors interact to form regulatory networks. The interactions between miRNAs and transcription factors have been shown to represent co-regulation network designs (adapted from Shalgi et al. [70]). As discussed in the text, feed-forward loops occur in high frequency in many biological networks and consist of a TF and miRNA that act as a switch. In the feed-forward loop diagrammed, a TF regulates its partner miRNA as well as target genes. Other more complex networks are also found, as described in Section 3 and [70].

Fig. 3

Cytokines may be regulated both directly and indirectly by miRNA. (A) Post-transcriptional regulation of the interleukin genes mediated via miRNA and ARE sites in the 3′UTR. Interleukin genes with predicted miRNA binding sites are indicated in the first box. Those with ARE sites [20] are listed in the second box where the text in red signifies predicted regulation by both miRNAs and AREs. (B) Indirect miRNA regulation of genes (e.g., cytokine genes) having AU-rich sites in their 3′UTR. miRNA potentially regulate the expression of the components of the ARE machinery. Additionally, MAPKs regulate the function of ARE-BPs and they may in turn be regulated by miRNA [5]. MiR-16 sites are found to overlap with some ARE sites and could potentially provide another mechanism by which miRNA regulate the expression of ARE-containing transcripts like SOCS3 (see Section 9).

Fig. 4

miRNAs provide a link between inflammation and cancer. miRNAs have been identified as having roles in the regulation of innate and adaptive immunity. Inflammatory mediators and cytokines can regulate miRNA expression which may contribute to the regulation of multiple genes. The regulatory networks formed include both feed forward and feedback loops and contribute to inflammation and oncogenesis.