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: 10.45). 02/2012; 119(15):3478-85. DOI: 10.1182/blood-2011-12-398099
Source: PubMed


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.

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    • "Since miR155 has been shown to play a critical role in regulation of T cell IFN-γ release [25], [28], we used miRNA155-/- mice in the following experiments to confirm whether miRNA155 is involved in T cell IFN-γ production. T cells were isolated from miRNA155-/- and wild-type mice and were analyzed first for miRNA155 expression to confirm that T cells from miRNA155-/- are indeed deficient in miRNA155. "
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    ABSTRACT: miRNA155 has been implicated in normal T cell function and their differentiations into the Th1 subtype. We have shown that acute alcohol (ethanol) intoxication combined with burn injury suppresses T cell IFN-γ release. Herein, we examined whether the decrease in IFN-γ is resulted from altered expression of miRNA155 and transcription factors -NFAT, Tbx21, Jun and Fos - in T cells following ethanol and burn injury. Mice received ethanol (∼3 g/Kg) 4 hours prior to ∼12.5% total body surface area sham or burn injury and were sacrificed one day after injury. Splenic T cells were harvested and cultured with anti-CD3 (2 µg/ml) in the presence or absence of rIL-12 (10 ng/ml) or PMA (10 ng/ml) plus ionomycin (50 ng/ml) for 48 hours. We observed a significant decrease in miRNA155, NFAT, Tbx21, Jun and Fos expression as well as IFN-γ release in T cells cultured with anti-CD3 following ethanol and burn injury compared with shams. The co-treatment of T cells with rIL-12 prevented the decrease in IFN-γ and NFAT, Tbx21, Jun and Fos, but not miRNA155. In contrast, the co-treatment with PMA plus ionomycin normalized the expression of NFAT. It did not prevent the decrease in IFN-γ, Tbx21, Jun, Fos and miRNA155. Finally, results obtained in miRNA155-/- mice did not show any change in T cell release of IFN-γ or expression of nuclear factors compared to wildtype mice. Together, these findings suggest that while ethanol and burn injury decreases the expression of miRNA155, it may not be involved in decreased IFN-γ under those conditions.
    PLoS ONE 08/2014; 9(8):e105314. DOI:10.1371/journal.pone.0105314 · 3.23 Impact Factor
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    • "This was associated to higher stability of the TF c-Myb, a direct target of miRNA-150 negatively regulated during the transition from CD27highCD11blow to CD27lowCD11bhigh NK cells (7). Similarly, miRNA-155 has been shown to enhance IFN-γ production in human NK cells activated by IL-2/IL-18 (24). Differently from miRNA-150, in miRNA-155−/− mice, the immature CD27highCD11blowLy49D−Ly49H−NK cell subset is reduced, likely because miRNA-155 targets the pro-apoptotic factor Noxa, thus supporting survival and homeostasis of developing NK cells (25). "
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    ABSTRACT: Chemokines play a fundamental role in lymphocyte development, mainly attributable to the control of the correct localization in the proper microenvironments of cells undergoing maturation. Natural killer (NK) cell development occurs in the bone marrow (BM) where their localization is regulated by the balance of chemokine function in cell retention into tissues and mobilization into circulation. In addition, NK cells from several extra-medullary tissues are phenotypically and functionally different from their circulating counterpart suggesting that maturation can be completed in organs other than BM. Indeed, a role of chemokines in NK cell localization into tissues during homeostatic conditions is also documented. In this review, we summarize the current notion related to the relevance of several chemokine/chemokine receptor axes in NK cell development with a focus on the regulation of their expression and function.
    Frontiers in Immunology 02/2014; 5:44. DOI:10.3389/fimmu.2014.00044
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    • "Moreover, Expression of 23 miRNAs was increased while 31 other miRNAs were downregulated after ex vivo expansion (Table 10). Interestingly, one of the miRNAs found to be upregulated was has-miR-155, which when overexpressed has been shown to increase NK cell function via enhanced induction of IFN-γ (Trotta et al., 2012). "
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    ABSTRACT: Recent clinical studies suggest that adoptive transfer of donor-derived natural killer (NK) cells may improve clinical outcome in hematological malignancies and some solid tumors by direct anti-tumor effects as well as by reduction of graft versus host disease (GVHD). NK cells have also been shown to enhance transplant engraftment during allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. The limited ex vivo expansion potential of NK cells from peripheral blood (PB) or umbilical cord blood (UCB) has however restricted their therapeutic potential. Here we define methods to efficiently generate NK cells from donor-matched, full-term human placenta perfusate (termed Human Placenta-Derived Stem Cell, HPDSC) and UCB. Following isolation from cryopreserved donor-matched HPDSC and UCB units, CD56+CD3- placenta-derived NK cells, termed pNK cells, were expanded in culture for up to 3 weeks to yield an average of 1.2 billion cells per donor that were >80% CD56+CD3-, comparable to doses previously utilized in clinical applications. Ex vivo-expanded pNK cells exhibited a marked increase in anti-tumor cytolytic activity coinciding with the significantly increased expression of NKG2D, NKp46, and NKp44 (p < 0.001, p < 0.001, and p < 0.05, respectively). Strong cytolytic activity was observed against a wide range of tumor cell lines in vitro. pNK cells display a distinct microRNA (miRNA) expression profile, immunophenotype, and greater anti-tumor capacity in vitro compared to PB NK cells used in recent clinical trials. With further development, pNK may represent a novel and effective cellular immunotherapy for patients with high clinical needs and few other therapeutic options.
    Frontiers in Immunology 05/2013; 4:101. DOI:10.3389/fimmu.2013.00101
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