Abstract
The discovery of miRNAs has revolutionized the way we examine the genome, RNA products, and the regulation of transcription and translation. Their ability to modulate protein expression through mRNA degradation and translation repression resulted in avid scientific interest in miRNAs over the past decade. This research has led to findings that indicate miRNAs can regulate an array of cellular functions such as cellular apoptosis, proliferation, differentiation, and metabolism. Specifically, the capability of miRNAs to finely-tune gene expression naturally lends itself to immune system regulation which requires precise control for proper activity. In fact, abnormal miRNAs expression is often seen with inflammatory disorders like rheumatoid arthritis, systemic lupus erthematosus, experimental autoimmune encephalomyelitis, and inflammatory cancers. As a result, research investigating miRNAs modulation of immune cell proliferation, differentiation, and cellular signaling has yielded fruitful results. Specifically, in this review, we will examine the impact of miRNAs on toll-like receptor (TLRs) and interleukin-1β (IL-1β) signaling, which are integral in the proper functioning of the innate immune system. These signaling pathways share several key downstream signaling adaptors and therefore produce similar downstream effects such as the production of pro-inflammatory cytokines, chemokines, and interferons. This review will examine in depth the specific interactions of miRNAs with receptors, adaptor molecules, and regulator molecules within these cellular pathways. In addition, we will discuss the modulation of miRNAs’ expression by TLR and IL-1R signaling through positive and negative feedback loops.
Highlights
The existence of a molecular system capable of orchestrating the expression of numerous proteins was postulated by researchers for some time; the discovery of microRNAs confirmed this hypothesis
Myeloid differentiation primary-response protein 88 (MyD88)-independent signaling pathway While mice deficient of MyD88 have displayed an inability to produce IL-6 or tumor necrosis factor-α (TNF-α) when exposed to toll-like receptor (TLR) microbial ligands or IL-1, more extensive experimentation with LPS resulted in delayed NF-kB activation and INF-β production
Taken into account that experiments with overexpressing miR-146 epithelial cells and fibroblasts resulted in a reduction of IL-1-induced cytokine expression, and that miR-146 is known to target the critical TLR/IL-1 signaling molecules IRAK1 and TRAF6, one can conclude that miR-146 is capable of mitigating a TLR/IL-1 inflammatory response in a negative feedback manner
Summary
The existence of a molecular system capable of orchestrating the expression of numerous proteins was postulated by researchers for some time; the discovery of microRNAs (miRNAs) confirmed this hypothesis. It should be noted that in the specific instances of TLR-2 and −4 signaling the association of another TIR-domain containing protein, MyD88 adaptor-like (MAL), facilitates the binding of MyD88. MyD88-independent signaling pathway While mice deficient of MyD88 have displayed an inability to produce IL-6 or TNF-α when exposed to TLR microbial ligands or IL-1, more extensive experimentation with LPS resulted in delayed NF-kB activation and INF-β production.
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