In mammalian cells, miRNAs (microRNAs) are the most abundant family of small non-coding RNAs that regulate mRNA translation through the RNA interference pathway. In general, it appears that the major function of miRNAs is in development, differentiation and homoeostasis, which is indicated by studies showing aberrant miRNA expression during the development of cancer. Interestingly, changes in the expression of miR-146a have been implicated in both the development of multiple cancers and in the negative regulation of inflammation induced via the innate immune response. Furthermore, miR-146a expression is driven by the transcription factor NF-κB (nuclear factor κB), which has been implicated as an important causal link between inflammation and carcinogenesis. In the present article, we review the evidence for a role of miR-146a in innate immunity and cancer and assess whether changes in miR-146a might link these two biological responses.

Introduction

miRNA (microRNA)-mediated RNA interference is a novel mechanism involved in the regulation of the gene expression at the translational level. At the present time, >700 human miRNAs have been identified (see the miRBase at http://microrna.sanger.ac.uk/sequences/) and shown to be involved in the regulation of a host of biological responses. These short double-stranded RNA sequences of 20–23 nt in length contain regions of non-complementarity and are produced by the processing of full-length transcripts. This involves the initial transcription of primary miRNAs by RNA polymerase II [1] to produce capped polyadenylated transcripts [2]. In the majority of cases, these are subsequently recognized and cleaved within a microprocessor complex that contains the type-2 RNase III enzyme Drosha [3,4], in combination with DGCR8 [57], to create a hairpin loop RNA of ∼65 nt known as pre-miRNA (precursor miRNA). However, recent studies have suggested that miRNAs located within intronic regions of protein-encoding genes can also be processed by the mRNA splicing system into so-called ‘mirtrons’ [810]. Both pre-miRNAs and mirtrons are then transported into the cytoplasm by exportin 5 [11] and cleaved by another type-2 RNase III enzyme, Dicer [1214], to produce duplex miRNA. The Dicer-loaded miRNA is then recruited to Ago (Argonaute)-2 protein by TRBP (HIV transactivating response RNA-binding protein) [15,16] to form the miRISC (miRNA-induced silencing complex). The Ago-2 protein is the effector component that initially cleaves the miRNA passenger strand (also called the * strand) and then uses the remaining mature single-stranded miRNA as a template to the target mRNA molecule [1720].

The innate immune response

The innate immune response provides the initial defence mechanism against infection by external pathogens such as bacteria, fungi and viruses. The presence of invading pathogens is commonly detected by tissue macrophages using families of pattern-recognition receptors, which recognize conserved molecular structures known as PAMPs (pathogen-associated molecular patterns). At the present time, multiple families of pattern-recognition receptors have been identified, including the TIR [Toll/IL (interleukin)-1 receptor] superfamily [21], the NLR (nucleotide-binding domain-like receptor) family [22] and the RLRs [RIG-I (retinoic acid-inducible gene I)-like receptors]. The best characterized is the TIR superfamily, which, in humans, can be subdivided into the TLRs (Toll-like receptors) that are composed of 11 members (named TLR-1 to TLR-11) and the IL-1 receptors which have ten members. The IL-1 receptor family are activated by the pro-inflammatory cytokines IL-1α, IL-1β and IL-18, whereas the TLRs recognize PAMPs including bacterial and fungal cell wall components such as lipoproteins (TLR-1/2), LPS (lipopolysaccharide) (TLR-4), flaggelin (TLR-5) and zymosan (TLR-6). Agonism of these receptors stimulates the production of protein- and lipid-based inflammatory mediators such as IL-1β, TNFα (tumour necrosis factor α), IL-8, RANTES (regulated upon activation, normal T-cell expressed and secreted), leukotrienes (LTB4 and LTC4) and prostaglandins (PGD2 and PGE2). TLRs also detect pathogen-derived oligonucleotides such as bacterial CpG motifs (TLR-9), viral single-stranded RNA (TLR-7/8) and double-stranded RNA (TLR-3), which additionally causes the production of IFN (interferon)-α/β. Following pathogen-mediated activation of macrophages, the release of inflammatory mediators activates surrounding cells such as epithelial and endothelial cells, fibroblasts and airway smooth muscle cells, which then in turn also release pro-inflammatory mediators. The result is the development of the classic symptoms of inflammation, including vasodilation/vasoconstriction, increased vascular permeability and the rapid recruitment of circulating leucocytes such as neutrophils and monocytes. Once within the tissue, neutrophils and resident macrophages phagocytose and kill invading bacteria and fungi, and cells infected with viruses, using degradative enzymes and ROS (reactive oxygen species) produced by the activation of the NADPH oxidase.

miRNAs and haemopoiesis

The first indication that miRNAs might be involved in the regulation of immunity were reports showing the selective expression of miR-223 in the bone marrow and evidence of its involvement in the differentiation of pluripotent haemopoietic stem cells into the various blood cell lineages [2326]. For example, differentiation to the granulocyte lineage is enhanced through the up-regulation of miR-223 by the transcription factor C/EBPα (CCAAT/enhancer-binding protein), and the subsequent inhibition of NFI-A (nuclear factor I-A) [27]. Differential miRNA expression was also shown in CD34+ haemopoietic progenitor cells [28], with miR-155 in particular inhibiting the differentiation of myeloid and erythroid cells. The importance of miRNA during haemopoiesis has been confirmed by subsequent reports that have demonstrated that the miR-1792 cluster, miR-146a, miR-155 and miR-223 are involved in the production of myeloid cells including neutrophils and monocytes [2731]. Moreover, miR-146a was demonstrated to be differentially expressed in murine Th1 and Th2 cells. High expression was observed in Th1 cells, but not in Th2 or naïve cells, suggesting that miR-146a is important in maintaining differentiated T-cell lineages [32]. In addition to haemopoiesis, studies have also shown that miR-146a [33,34] and miR-155 [33,3537] regulate the acute innate immune response following activation via the TIR superfamily [38].

miR-146a and the innate immune response

The miR-146 family is composed of two members, miR-146a and miR-146b that are located on chromosomes 5 and 10 respectively. Evidence that miR-146a might be involved in the innate immune response was first reported by Taganov et al. [33] who showed increased expression in the human monocytic THP-1 cell line in response to LPS-induced TLR-4 activation. Subsequent studies have shown that this is a general response in myeloid cells activated through TLR-2, -4 or -5 by bacterial and fungal components or following exposure to the pro-inflammatory cytokines TNFα or IL-1β [33,35,36]. In contrast, miR-146a expression was not increased following activation of TLR-3, -7 or -9 in response to viral or bacterial nucleic acids [33]. Our own studies indicate that IL-1β induced a rapid increase in miR-146a in a range of lung-associated cells, including alveolar epithelial A549 cells, airway epithelial BEAS2B cells, primary human airway epithelial cells and primary human airway smooth muscle cells [34], whereas Nakasa et al. [39] have reported that TNFα and IL-1β induced miR-146a expression in human rheumatoid arthritis synovial fibroblasts.

Transcriptional studies have shown that TIR-mediated miR-146a expression is predominantly driven by NF-κB (nuclear factor κB) [33,40]. In contrast, little is known regarding miR-146a function and mechanism. Using alveolar A549 epithelial cells, we showed that the increases in miR-146a expression negatively regulate the IL-1β-induced release of chemokines, IL-8 and RANTES. Significantly, this negative feedback was only seen at high IL-1β concentrations, which indicated that this might be an important mechanism during severe inflammation [34]. To elucidate the mechanism by which miR-146a might negatively regulate IL-8 and RANTES release, examination of the public databases predicted a number of potential targets. Prominent among these are IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6), which are known to be part of the common signalling pathway of the TIR superfamily. However, although we [34] and others [33,41,42] have reported down-regulation of IRAK1 and/or TRAF6 following miRNA-146a overexpression, this does not appear to be responsible for the responses seen following either IL-1β exposure or HBV (hepatitis B virus) infection. Instead, in the case of IL-1β stimulation, it appears that miR-146a is involved in either direct or indirect targeting of IL-8 and RANTES translation [34].

miR-146a and inflammatory disease

Recent reports have indicated elevated basal miR-146a expression in the tissues associated with chronic inflammatory diseases such as psoriasis [43] and rheumatoid arthritis [39,44], which is likely to reflect the infiltration of inflammatory cells and increased levels of mediators such as TNFα and IL-1β. In the case of rheumatoid arthritis, miR-146a was found to localize to superficial and sub-lining layers in the synovial tissue and within CD68+ macrophages, CD3+ T-cell subsets and CD79a+ B-cells [39]. The expression of miR-146, and miR-155, was found to be higher in rheumatoid arthritis synovial fibroblasts compared with fibroblasts from osteoarthritis patients [44], indicating that these miRNAs are indeed associated with inflammatory diseases. Elevated levels of miR-155 could also be induced in fibroblasts stimulated with TNFα, IL-1β and several TLR ligands. However, increased miR-146a expression was only induced following LPS or IL-1β stimulation and not with TNFα or other TLR ligands, suggesting that the induction of miR-146a in response to inflammatory stimuli is cell-type- and ligand-specific. Similarly, psoriasis has been characterized by a specific miRNA expression profile [43], including overexpression of miR-203 and miR-146a. It seems that miR-203 is associated with an inhibition of SOCS3 (suppressor of cytokine signalling 3) specifically within keratinocytes, whereas miR-146a was most highly expressed in CD4+CD25+ T-cells. This latter observation may suggest that miR-146a has an important function in the differentiation or maintenance of CD4+ T regulatory cells, emphasizing further its role as a negative regulator of inflammation. Interestingly, miR-146a levels were not increased in tissues obtained from patients with other chronic inflammatory diseases such as the skin from atopic eczema [43] or lung biopsies from mild asthmatics (results not shown).

miRNA-146a and cancer

Chronic infection with EBV (Epstein–Barr virus) has been implicated in the development of a number of malignancies, including Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease, in immunosuppressed individuals. Expression of the EBV LMP1 (latent membrane protein 1), which functionally mimics TNF receptors, has been shown to induce miR-146a. This led to speculation that aberrant expression of miR-146a might be linked to the development of cancerous phenotypes [40,45]. Indeed, this contention is supported by reports of elevated miR-146a levels in PTC (papillary thyroid carcinoma) [41,46,47], cervical cancer [48], breast cancer [49] and pancreatic cancer [49], whereas reduced miR-146a expression is associated with prostate cancer [49,50]. Interestingly, it has been suggested that the changes in miR-146a expression observed in these solid tumours could be related to a common G/C polymorphism (designated rs2910164) located within the stem–loop of pre-miR-146a [51]. Examination of the free binding energy predicts that the minor C allele should result in reduced base pairing and that this might have an impact on the miRNA-processing pathway. Measurement of the expression of the two alleles in cells have produced contradictory conclusions, with reports that the C variant both increases [52] and decreases [41] the levels of pre-miR-146a and miR-146a expression. Genetic association studies have also produced conflicting conclusions. Thus, although one report indicated that this polymorphism did not appear to be linked with an increased risk of breast cancer [53], another showed that those breast and ovarian cancer patients with at least one C allele (GC or CC) were diagnosed at a younger age [52]. In contrast, heterozygosity (GC) but not homozygosity (GG or CC) was associated with increased risk of PTC, whereas comparison of normal and cancerous tissue indicated that somatic mutation from CC/GG to GC is observed in 3–6% of samples obtained from PTC patients [41].

At the present time, it is unknown whether changes in miR-146a expression are causally linked to the development of cancer. It is now well established that chronic inflammation and the activation of NF-κB is associated with development of multiple cancers [54]. It might therefore be speculated that activated NF-κB, rather than the common G/C polymorphism is responsible for increased miR-146a expression. Expression might also be driven by other signalling pathways, since multiple transcriptional binding sites have been identified upstream of the miR-146a gene [33,40]. Mechanistically, it has been suggested that increased miR-146a expression might be linked to cancer through inappropriate regulation of the inflammatory response. However, it would seem unlikely that the action of miR-146a is mediated through down-regulation of the NF-κB pathway given that this has been shown to prevent the development of cancer. Indeed, lentiviral-mediated expression of miR-146a in the human breast cancer cell line MDA-MB-231 and down-regulation of IRAK1 and TRAF6 were shown to inhibit tumour cell invasion and migration [42]. Interestingly, cells transfected with EBV LMP1 showed down-regulation of multiple genes involved in the IFN-α/β response and the authors speculated that miR-146a-mediated immune suppression might lead to increased survival of cancerous cells [40]. Similarly, miR-146a is up-regulated in cervical cancer tissue, and introduction of miR-146a into cervical cancer cell lines increased cell proliferation [48]. As an alternative to targeting inflammation, increased expression of ROCK1 (Rho-activated protein kinase 1) has been suggested as the link between reduced miR-146a levels and development of prostate cancer. Thus studies in the prostate cancer PC3 cell line have shown that miR-146a targets ROCK1, and that elevated ROCK1 expression caused increases in cell proliferation, invasion and metastasis [50].

Conclusions

There is now increasing evidence to suggest that miR-146a is involved in the regulation of the innate immune response. However, despite numerous studies that show the induction of miR-146a expression by pro-inflammatory mediators, there is still little information regarding its role and mechanism of action. Tackling these questions therefore remains an essential task and will probably involve the production of transgenic and/or knockout animals. Importantly, this approach will also provide information regarding the link between chronic changes in miR-146a levels and the development of carcinogenesis, since the existing evidence is weak and contradictory.

MicroRNAs and the Regulation of Biological Function: A Biochemical Society Focused Meeting held at Imperial College London, U.K., 8 July 2008. Organized and Edited by Tamas Dalmay (University of East Anglia, U.K.), Mark Lindsay (Imperial College London, U.K.) and Sterghios Moschos (Imperial College London, U.K.).

Abbreviations

     
  • Ago

    Argonaute

  •  
  • EBV

    Epstein–Barr virus

  •  
  • IFN

    interferon

  •  
  • IL

    interleukin

  •  
  • IRAK1

    IL-1 receptor-associated kinase 1

  •  
  • LMP1

    latent membrane protein 1

  •  
  • LPS

    lipopolysaccharide

  •  
  • miRNA

    microRNA

  •  
  • pre-miRNA

    precursor miRNA

  •  
  • NF-κB

    nuclear factor κB

  •  
  • PAMP

    pathogen-associated molecular pattern

  •  
  • PTC

    papillary thyroid carcinoma

  •  
  • RANTES

    regulated upon activation, normal T-cell expressed and secreted

  •  
  • ROCK1

    Rho-activated protein kinase 1

  •  
  • TIR

    Toll/IL-1 receptor

  •  
  • TLR

    Toll-like receptor

  •  
  • TNF

    tumour necrosis factor

  •  
  • TRAF6

    TNF receptor-associated factor 6

A.E.W. and M.A.L. are supported by the Wellcome Trust (076111), M.M.P. is supported by Asthma UK (07/015) and H.M.L.-S. is support by an NHLI (National Heart and Lung Institute) Ph.D. fellowship.

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