ABSTRACT
Regulation of innate immune responses is essential for maintenance of immune homeostasis and development of an appropriate immunity against microbial infection. We show here that miR-3614-5p, product of the TRIM25 host gene, is induced by type I interferon (IFN-I) in several human non-immune and immune cell types, in particular in primary myeloid cells. Studies in HeLa cells showed that miR-3614-5p represses both p110 and p150 ADAR1 and reduces constitutive and IFN-induced A-to-I RNA editing. In line with this, activation of innate sensors and expression of IFN-ß and the pro-inflammatory IL-6 are promoted. MiR-3614-5p directly targets ADAR1 transcripts by binding to one specific site in the 3'UTR. Moreover, we could show that endogenous miR-3614-5p is associated with Ago2 and targets ADAR1 in IFN-stimulated cells. Overall, we propose that, by reducing ADAR1, IFN-I-induced miR-3614-5p contributes to lowering the activation threshold of innate sensors. Our findings provide new insights into the role of miR-3614-5p, placing it as a potential fine tuner of dsRNA metabolism, cell homeostasis and innate immunity.
Subject(s)
Adenosine Deaminase/metabolism , Immunity, Innate , Interferon Type I , MicroRNAs , RNA-Binding Proteins/metabolism , Transcription Factors/genetics , Tripartite Motif Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Antibodies , Antiviral Agents , HeLa Cells , Humans , MicroRNAs/genetics , Protein Isoforms , RNA, Double-StrandedABSTRACT
This article examines the assumptions used to support the strategic and tactical use of clinical trial data as the main type of information provided by pharmaceutical marketers. Evidence is presented which suggests that doctors use clinical trial data to construct general beliefs about a disease or product and that it is often used incorrectly when assessing the probability that a patient has a specific disease. Further evidence is examined which suggests that clinical experience is the most important type of information used when doctors make specific prescription decisions. A call is made for the pharmaceutical industry to address the need for experiential information by examining ways to provide doctors with detailed patient case histories.