miR-155 regulates IFN-γ production in natural killer cells.

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
Blood (Impact Factor: 9.78). 02/2012; 119(15):3478-85. DOI: 10.1182/blood-2011-12-398099
Source: PubMed

ABSTRACT MicroRNAs (miRs) are small, noncoding RNA molecules with important regulatory functions whose role in regulating natural killer (NK) cell biology is not well defined. Here, we show that miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. Over-expression of miR-155 enhanced induction of IFN-γ by IL-12 and IL-18 or CD16 stimulation, whereas knockdown of miR-155 or its disruption suppressed IFN-γ induction in monokine and/or CD16-stimulated NK cells. These effects on the regulation of NK cell IFN-γ expression were found to be mediated at least in part via miR-155's direct effects on the inositol phosphatase SHIP1. Consistent with this, we observed that modulation of miR-155 overrides IL-12 and IL-18-mediated regulation of SHIP1 expression in NK cells. Collectively, our data indicate that miR-155 expression is regulated by stimuli that strongly induce IFN-γ in NK cells such as IL-12, IL-18, and CD16 activation, and that miR-155 functions as a positive regulator of IFN-γ production in human NK cells, at least in part via down-regulating SHIP1. These findings may have clinical relevance for targeting miR-155 in neoplastic disease.

  • [Show abstract] [Hide abstract]
    ABSTRACT: microRNAs (miRNAs) are short, single-stranded RNA molecules that function together with the partner proteins and cause degradation of target mRNAs or inhibit their translation. A particular miRNA can have hundreds of targets; therefore, miRNAs cumulatively influence the expression of a large proportion of genes. The functions of miRNAs in human diseases have been studied since their discovery in mammalian cells approximately 12 years ago. However, the role of miRNAs in allergic disease has only very recently begun to be uncovered. The purpose of this review is to provide an overview of the functions of miRNAs involved in the development of allergic diseases. We describe here the functions of miRNAs that regulate Th2 polarization and influence general inflammatory and tissue responses. In addition, we will highlight findings about the functions of extracellular miRNAs as possible noninvasive biomarkers of diseases with heterogeneous phenotypes and complex mechanisms and briefly discuss advances in the development of miRNA-based therapeutics.
    Current Allergy and Asthma Reports 04/2014; 14(4):424. · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: miRNAs are small noncoding RNAs with gene regulatory functions, frequently dysregulated in human cancers. Specific signatures of differentially expressed miRNAs can be used in the diagnosis of cancer and in some cases harbor prognostic implications. The biology of cancer is dictated not only by cancer cells but also by the surrounding tumor microenvironment. In particular, the role of miRNAs within the tumor microenvironment is emerging as of paramount importance. This review will focus on the current knowledge of the role of miRNAs and both cellular and stromal components of the tumor microenvironment. We will also discuss more recent findings, showing that miRNAs can be found inside of exosomes and mediate the cross-talk between cancer cells and surrounding cells, leading to the discovery of new fascinating molecular mechanisms leading to a better understanding of the cancer 'niche' and how these noncoding RNAs can become very promising diagnostic molecules.
    Expert Review of Molecular Diagnostics 06/2014; 14(5):565-74. · 4.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interferons (IFNs) are low molecular weight cell-derived proteins that include the type I, II, and III IFN families. IFNs are critical for an optimal immune response during microbial infections while dysregulated expression can lead to autoimmune diseases. Given its role in disease, it is important to understand cellular mechanisms of IFN regulation. 3' untranslated regions (3' UTRs) have emerged as potent regulators of mRNA and protein dosage and are controlled through multiple regulatory elements including adenylate uridylate (AU)-rich elements (AREs) and microRNA (miRNA) recognition elements. These AREs are targeted by RNA-binding proteins (ARE-BPs) for degradation and/or stabilization through an ARE-mediated decay process. miRNA are endogenous, single-stranded RNA molecules ∼22 nucleotides in length that regulate mRNA translation through the miRNA-induced silencing complex. IFN transcripts, like other labile mRNAs, harbor AREs in their 3' UTRs that dictate the turnover of mRNA. This review is a survey of the literature related to IFN regulation by miRNA, ARE-BPs, and how these complexes interact dynamically on the 3' UTR. Additionally, downstream effects of these post-transcriptional regulators on the immune response will be discussed. Review topics include past studies, current understanding, and future challenges in the study of post-transcriptional regulation affecting IFN responses.
    Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 04/2014; · 1.63 Impact Factor