Regulation of Eicosanoid Pathways by MicroRNAs

Abstract

Over the last years, many microRNAs (miRNAs) have been identified that regulate the formation of bioactive lipid mediators such as prostanoids and leukotrienes. Many of these miRNAs are involved in complex regulatory circuits necessary for the fine-tuning of biological functions including inflammatory processes or cell growth. A better understanding of these networks will contribute to the development of novel therapeutic strategies for the treatment of inflammatory diseases and cancer. In this review, we provide an overview of the current knowledge of miRNA regulation in eicosanoid pathways with special focus on novel miRNA functions and regulatory circuits of leukotriene and prostaglandin biosynthesis.

Keywords: eicosanoids; inflammation; microRNA; new miRNA functions; prostaglandins.

Figure 1

Overview of miRNA functions. The mature miRNA can be incorporated into the RNA-induced silencing complex (RISC) and binds to its target mRNA (A) to repress translation or (B) to induce mRNA degradation—for example, endonucleolytic cleavage. (C) miRNAs can act as RNA decoy to RNA-binding proteins, such as miR-328 to hnRNP E2 or miR-574-5p to CUGBP1. (D) miRNAs can be recognized by toll-like receptors 7/8, like miR-21 and miR-29a.

Figure 2

Schematic overview of the leukotriene and prostanoid biosynthesis pathway. Arachidonic acid (AA) is released from cellular membranes by cytosolic phospholipase A₂ (PLA₂). The free AA can further be converted to different leukotrienes (LT). 5-LO is crucial for the conversion of AA to 5(S)-hydroperoxyeicosatetraenoic acid (5-HPETE) and LTA₄. LTA₄ is further converted to LTB₄ by LTA₄ hydrolase (LTA₄H) or to the cysteinyl-containing LTC₄ by LTC₄ synthase (LTC₄S), which can be metabolized to LTD₄ and LTE₄. Biosynthesis of prostanoids begins with the enzyme cyclooxygenase (COX)-1 or COX-2 converting AA to prostaglandin (PG) H₂, which is further converted to a variety of other prostanoids. Thromboxane A₂ (TXA₂) is generated by TXA synthase (TXAS), while the synthases PGxS produce the certain PGs: PGF_2α, PGI₂, and PGD₂. The microsomal PGE synthase-1 (mPGES-1) catalyzes formation of PGE₂.

Figure 3

Regulatory circuits of leukotriene and prostaglandin biosynthesis. (A) miR-574-5p/CUGBP1 regulates mPGES-1 level, (B) miR-16/HuR and (C) miR-146a modulate COX-2 expression. (D) miR-125 and (E) miR-19a regulate 5-LO level. Stimulation is indicated by blue arrows, whereas red lines indicate inhibition.