However, at the time of discovery, it was assumed that these RNAs were rare exceptions and only present in nematodes. In , three independent publications reported the existence of several hundreds of these small non-coding RNAs not only in nematodes but also in murine and human cells Lagos-Quintana et al.

In this review, we will give a short overview of novel miRNA functions involved in inflammatory processes. Moreover, we summarize the recent findings on miRNAs regulating key enzymes of the eicosanoid signaling pathway. In the nucleus, these pri-miRNAs are subsequently cleaved by the endonuclease Drosha. Drosha generates about 70 nucleotide nt long precursors pre-miRNAs that form imperfect stem-loop structures. Pre-miRNAs are transported out of the nucleus by exportin The passenger strand is mostly rapidly degraded.

Subsequently, they mediate endonucleotic cleavage, translational repression, or deadenylation of the mRNA transcript, followed by decapping and degradation of the target mRNA Filipowicz et al. Figure 1 Overview of miRNA functions. Traditionally, it has been assumed that miRNAs are loaded into RISC and bind to their target mRNA through specific base pairing and that they reduce gene expression at the post-transcriptional level as their sole canonical function.

However, there is recent evidence that miRNAs are also able to activate gene expression via a non-canonical mechanism Figures 1C, D. As a consequence, hnRNP E2 target gene expression is activated. Recent findings demonstrate that cells can secrete bioactive molecules like proteins, lipids, or nucleic acids from cell to cell via extracellular vesicles. Those vesicles can be divided into small extracellular vesicles sEVs, also known as exosomes , microvesicles or apoptotic vesicles distinguished by their size Thery et al.

Different cell types, including immune and cancer cells, are capable of secretion and uptake of extracellular miRNAs from sEVs. This suggests that sEVs could be part of the intercellular communication and carry out novel biological functions. Similar results were found for miRNA let-7b in the context of the nervous system.

Extracellular let-7b activates murine TLR7 and induces neurodegeneration. An interesting aspect for further investigations in this context is to explore how miRNAs are sorted into EVs. These data suggest that the loading of miRNAs into EV is a specific process that might control biological processes such as immune functions. Eicosanoids such as prostaglandins and leukotrienes are biologically active lipid mediators that are products of a local cell type-specific arachidonic acid AA metabolism Figure 2.

Such lipid mediators play a critical role in different pathological processes like inflammation and cancer Zeldin, ; Wang and Dubois, ; Radmark et al. The synthesis of eicosanoids begins with the release of AA from the cell membrane by phospholipase A 2 which is followed by the metabolism of the AA through cyclooxygenases COXs , lipoxygenases LOXs , and cytochrome P enzymes Wang and Dubois, Due to the key role of these enzymes in the formation of bioactive lipid mediators, it is not surprising that 5-LO and COX enzymes are prominent miRNA targets for previous reviews, see also Ochs et al.

Figure 2 Schematic overview of the leukotriene and prostanoid biosynthesis pathway. The free AA can further be converted to different leukotrienes LT. The group of prostanoids consists of prostaglandins, thromboxane A 2 , as well as prostacyclin. This intermediate is then converted to the different prostaglandins by the respective synthases.

Prostanoids belong to the most important inflammatory signaling molecules. These lipid mediators exert their multiple biological effects in an autocrine and paracrine manner by binding to their specific cell surface G protein-coupled receptors. For example, prostaglandin E 2 PGE 2 is a bioactive lipid that can elicit a wide range of biological effects associated with inflammation and cancer Jakobsson et al.

It contributes to the development of inflammation and plays a predominant role in promoting cancer progression by induction of cellular proliferation and tumor angiogenesis, inhibition of apoptosis, and suppression of immune responses Wang and Dubois, ; Larsson and Jakobsson, The formed PGE 2 is then rapidly secreted to act on their specific receptors on recipient cells. These receptors are not only present on immune cells, but also on a variety of cells of the cardiovascular system like cardiomyocytes, smooth muscle cells, or vascular endothelial cells Suzuki et al.

Thus, PGE 2 can be involved in the development of different cardiovascular diseases. It was shown that deletion of mPGES-1 impairs the left ventricular contractile function after acute myocardial infarction and leads to overall remodeling of the left ventricle Degousee et al.

Figure 3 Regulatory circuits of leukotriene and prostaglandin biosynthesis. Stimulation is indicated by blue arrows, whereas red lines indicate inhibition. There are two known isoenzymes responsible for the generation of prostanoids: cyclooxygenase-1 COX-1 and cyclooxygenase-2 COX-2 , both of which catalyze the same enzymatic reaction.

COX-1 represents a housekeeping enzyme responsible for maintaining basal prostanoid levels, which are important for tissue homeostasis. In contrast, COX-2 is barely detectable in most normal tissues, but is strongly induced in response to inflammatory cytokines, hypoxia, and other stressors Samuelsson et al. COX-2 expression is regulated at different levels Dixon et al.

At the post-transcriptional level, COX-2 expression is regulated by mRNA stability and translation efficiency mostly including trans - and cis-acting factors Dixon et al. In recent years, miRNAs have been identified as additional players in the post-transcriptional control of COX-2 expression see Table 1. The amnion is the major source of PGE 2 and plays a central role in the process of premature labor. The transcription factor c-fos induces expression of COX-2 and miR The latter in turn generates a negative feedback loop by directly and indirectly inhibiting both COX-2 and c-fos.

This inhibition has a negative effect on PGE 2 generation and thus prevents premature contractions Li et al. A negative correlation of miRp and COX-2 was also observed in human inflamed gingival tissue from periodontitis patients Li et al.

Moreover, a significant downregulation of miR and miRa compared to healthy surrounding tissue was found in the tumor tissue of patients with esophageal squamous cell carcinoma ESCC. It has been shown that, due to downregulation of miR and miRa in tumor tissue, COX-2 activity significantly increased and subsequently promoted cell proliferation and metastasis Shao et al. It was further demonstrated that the mechanism by which CSE regulates COX-2 expression is mediated by miRp to promote cell proliferation Gong et al.

In human fibroblasts of smokers with chronic obstructive pulmonary disease, it was found that single nucleotide polymorphisms in the miRa precursor caused several patients to have reduced miRNA level, which significantly improved baseline lung function Wang et al.

Very recently, it was demonstrated that the polymorphisms of miRa rs and plasmacytoma variant translocation 1 PVT1; rs affect the prognosis of colon cancer by regulating COX-2 expression and cell apoptosis.

Another miRNA that suppresses inflammation-related tumors is miRa. In the same way, colorectal cancer is influenced by miRa-3p, which directly targets COX-2 via its canonical function Wang et al.

The finding that miR directly regulates PDGH was further confirmed by recent publications on tongue squamous cell carcinoma He et al.

Interestingly, epithelial growth factor EGF signaling in colorectal cancer cells reduces the level of PGDH and simultaneously increases the miR level Monteleone et al. Furthermore, miR directly regulates the expression level of PGDH during differentiation of synovial mesenchymal stem cells SMSCs into cartilage and subsequently inhibits osteogenesis during chondrogenesis Cong et al. Finally, PDGH was identified as the canonical target of miRb-3p that promotes proliferation, migration, and anchorage-independent growth of cervical cancer cells Yao et al.

In addition to the regulation of the enzymes of the prostaglandin pathway by miRNAs, the influence of prostaglandin signaling on miRNA expression has also been investigated. It was found that COX-2 signaling increases the oncogenic miRb and miR levels in human breast cancer by activating the EP4 receptor. Thus, COX-2 signaling strongly influences the phenotype of the tumor by promoting cellular migration, invasion, or proliferation Majumder et al.

In addition, it was found that cancer-associated fibroblasts CAFs develop a senescence-associated secretory phenotype SASP that contributes to cancer progression. Moreover, miR is upregulated in the senescent normal fibroblasts as well as CAFs. This modulates the secretion of SASP factors and induces the mobility of cancer cells in co-cultures, at least partially by suppressing the expression of the phosphatase and tensin homologue PTEN.

It is noteworthy that PGE 2 -mediated downregulation of miRa and miR is directly associated to vascular endothelial growth factor VEGF expression and angiogenesis. This suggests that these miRNAs may be potential candidates for mitigating the aggressive properties of prostate cancer. The 5-lipoxygenase 5-LO is the key enzyme of the leukotriene pathway. Over the last decades, different studies have shown that 5-LO-derived AA metabolites play an important role in inflammatory reactions like inflammatory disorders and allergic diseases such as asthma, allergic rhinitis, cardiovascular diseases, as well as in different types of cancer Steinhilber and Hofmann, Furthermore, several publications demonstrated that 5-LO is a canonical target for miRa-3p, miRp Busch et al.

Overall, it reveals that miRa-3p and miRb-5p target 5-LO in a cell type and stimulus-specific manner Busch et al. Interestingly, miR and miRa seem to be parts of regulatory circuit-controlling immune reactions and cell proliferation Figures 3D, E. The same signals were also reported to induce miR Curtale et al. Thus, upregulation of miRa and downregulation of 5-LO expression are associated with cell proliferation in T-lymphocytes Busch et al. Furthermore, it is well known that upregulation of miRa inhibits cell differentiation and promotes cell growth and cancer development—for instance, by suppression of PTEN Lewis et al.

It is further discussed as a negative regulator in 5-LO-mediated autoimmune diseases of the liver, thus representing a promising approach to future therapeutic measures Su et al. Recently, it was shown that miRa-3p regulates not only COX-2 but also 5-LO expression in colon cancer, thus affecting colon cancer cell proliferation.

These data indicate that miRp might represent a novel target for colorectal cancer treatment Wang et al. Moreover, miRa is also known to regulate COX-2 expression in lung cancer Cornett and Lutz, , which indicates a role of miRa as an endogenous dual inhibitor of AA metabolism in lung cancer by regulating prostaglandins and LTs, similar to miRa-3p Iacona et al.

It is well known that 5-LO interacts with the C-terminal domain of human Dicer. The interaction between 5-LO and Dicer leads to an enhanced 5-LO enzymatic activity as well as Dicer activity in vitro. The number of miRNAs that were discovered in recent years to be involved in the regulation of the expression of key enzymes in prostanoid and LT biosynthesis is steadily increasing.

Tables 1 , 2 give a comprehensive overview of all currently known miRNAs involved in inflammatory processes. There is growing evidence that many of these miRNAs are involved in complex regulatory cascades and networks with multiple layers of integrated signals and feedback loops required for fine-tuning of biological functions such as inflammatory responses or cell growth. It becomes clear that miRNAs can also be packed into EVs so that they are involved in cell—cell communication.

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Meslier, N. Lipid mediators are also involved in multiple pathologies including cancer, autoimmunity or asthma. The pathological roles of lipid mediators are based on their intricate involvement in the immune system, which comprises source and target cells of these mediators.

Based on their biosynthetic origin, bioactive lipids can be grouped into different classes [e.