MiR-155 regulates IFN-γ production in natural killer cells
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.
- SourceAvailable from: Ruozhen Hu
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- "While studies carried out by our lab and others have provided evidence that these miRNAs oppose one another within T cells, it is also likely that miR-155 and miR-146a impact antitumor immune responses by also acting in non-T cell types, such as macrophages, dendritic cells and NK cells, where they have been shown to be expressed and to impact inflammatory responses (Boldin et al., 2011a; Cubillos-Ruiz et al., 2012; O'Connell et al., 2007; Trotta et al., 2012). Once conditional knockout mice are available for miR-155 and miR-146a then studies can be carried out to specifically test the relative contributions of these miRNAs to the functions of distinct cell types that drive tumor immunity, and this will shed additional light on the cellular basis of the observed epistasis. "
ABSTRACT: An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs), miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ) responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO) mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155(-/-) mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4(+) and CD8(+) T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses.Cell Reports 11/2012; 2(6). DOI:10.1016/j.celrep.2012.10.025 · 8.36 Impact Factor
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ABSTRACT: Natural killer (NK) cells play a critical role in early host defense to infected and transformed cells. Here, we show that mice deficient in Eri1, a conserved 3'-to-5' exoribonuclease that represses RNA interference, have a cell-intrinsic defect in NK-cell development and maturation. Eri1(-/-) NK cells displayed delayed acquisition of Ly49 receptors in the bone marrow (BM) and a selective reduction in Ly49D and Ly49H activating receptors in the periphery. Eri1 was required for immune-mediated control of mouse CMV (MCMV) infection. Ly49H(+) NK cells deficient in Eri1 failed to expand efficiently during MCMV infection, and virus-specific responses were also diminished among Eri1(-/-) T cells. We identified miRNAs as the major endogenous small RNA target of Eri1 in mouse lymphocytes. Both NK and T cells deficient in Eri1 displayed a global, sequence-independent increase in miRNA abundance. Ectopic Eri1 expression rescued defective miRNA expression in mature Eri1(-/-) T cells. Thus, mouse Eri1 regulates miRNA homeostasis in lymphocytes and is required for normal NK-cell development and antiviral immunity.Blood 05/2012; 120(1):130-42. DOI:10.1182/blood-2011-11-394072 · 10.43 Impact Factor
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ABSTRACT: Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP. Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes. In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.PLoS Neglected Tropical Diseases 07/2012; 6(7):e1729. DOI:10.1371/journal.pntd.0001729 · 4.49 Impact Factor