MicroRNAs activate natural killer cells through Toll-like receptor signaling

He, Shasha; Chu, Jianhong; Wu, Lai-Chu; Mao, Hsiaoyin; Peng, Yong; Alvarez‐Breckenridge, Christopher; Hughes, Tiffany; Min, Wei; Zhang, Jianying; Yuan, Shunzong; Sandhu, Sumeet; Vasu, Sumithira; Benson, Don M.; Hofmeister, Craig C.; He, Xiaoming; Ghoshal, Kalpana; Devine, Steven M.; Caligiuri, Michael A.; Yu, Jianhua

doi:10.1182/blood-2012-07-441360

Cited by 77 publications

(61 citation statements)

References 37 publications

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“…Therefore, we next determined whether TLRs mediated PL-C-induced IFN-γ production by human NK cells. Others and we have found that human NK cells mainly express TLR1, TLR3, and TLR6 (41, 54). We thus started the experiment by antibody blocking of these TLRs.…”

Section: Resultsmentioning

confidence: 76%

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The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human NK Cells through Upregulation of TLR-Mediated NF-κB Signaling

Deng

Chu

Ren

et al. 2014

The Journal of Immunology

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Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer initiating cells, and clear viral infections. However, few reports describe a natural product that selectively stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 mg/ml, and stimulated IFN-γ production in both human CD56bright and CD56dim NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C’s activation of the NF-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12/IL-15 receptors and their related STAT signaling pathways were not significantly modulated by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively activate human NK cell IFN-γ. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted.

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Section: Resultsmentioning

confidence: 76%

“…Human PBMCs and NK cells were freshly isolated from leukopaks (American Red Cross, Columbus, OH) as described previously (41). PBMCs were isolated by Ficoll-Paque Plus (GE Healthcare Bio-Sciences, Pittsburgh, PA) density gradient centrifugation.…”

Section: Methodsmentioning

confidence: 99%

The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human NK Cells through Upregulation of TLR-Mediated NF-κB Signaling

Deng

Chu

Ren

et al. 2014

The Journal of Immunology

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“…NF-κB activation and further activate human NK cells directly. For the role of NF-κB in NK cell activation, we propose that the activation of NF-κB signaling would enhance the activation or cytotoxicity of NK cells by promotion of IFN-γ production and perforin or granzyme expression as previously reported [23][24][25]. Moreover, the stimulation of TLR7 and TLR8 signaling can lead to the overall activation and maturation of APCs, such as macrophages and DCs, accompanied by high expression of co-stimulatory molecules and secretion of pro-inflammatory cytokines and type I IFN, and further fully activate effector NK, NKT and T cells to drive more potent immune responses [6].…”

Section: Discussionmentioning

confidence: 84%

TLR7/8 agonists promote NK–DC cross-talk to enhance NK cell anti-tumor effects in hepatocellular carcinoma

Zhou

Zhang

et al. 2015

Cancer Letters

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“…Whether at the mRNA or protein level, export of such molecules may offer a duel immune evasion strategy in which tumors can increase proliferation while inhibiting immune effector cell cytolytic activity. Finally, recent evidence indicates that circulating specific exogenous miRs, which are also packaged in exosomes, can modify NK cell function (52), and several miRs including miR-21, miR-26a, miR-214, miR-221, and miR-222 have each been shown to negatively regulate PTEN (36,(53)(54)(55)(56). This creates several potential therapeutic targets for enhancing NK cell function that warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

PTEN Is a Negative Regulator of NK Cell Cytolytic Function

Briercheck

Trotta

Chen

et al. 2015

The Journal of Immunology

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Human NK cells are characterized by their ability to initiate an immediate and direct cytolytic response to virally infected or malignantly transformed cells. Within human peripheral blood, the more mature CD56dim NK cell efficiently kills malignant targets at rest, whereas the less mature CD56bright NK cells cannot. In this study, we show that resting CD56bright NK cells express significantly more phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein when compared with CD56dim NK cells. Consistent with this, forced overexpression of PTEN in NK cells resulted in decreased cytolytic activity, and loss of PTEN in CD56bright NK cells resulted in elevated cytolytic activity. Comparable studies in mice showed PTEN overexpression did not alter NK cell development or NK cell–activating and inhibitory receptor expression yet, as in humans, did decrease expression of downstream NK activation targets MAPK and AKT during early cytolysis of tumor target cells. Confocal microscopy revealed that PTEN overexpression disrupts the NK cell’s ability to organize immunological synapse components including decreases in actin accumulation, polarization of the microtubule organizing center, and the convergence of cytolytic granules. In summary, our data suggest that PTEN normally works to limit the NK cell’s PI3K/AKT and MAPK pathway activation and the consequent mobilization of cytolytic mediators toward the target cell and suggest that PTEN is among the active regulatory components prior to human NK cells transitioning from the noncytolytic CD56bright NK cell to the cytolytic CD56dim NK cells.

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MicroRNAs activate natural killer cells through Toll-like receptor signaling

Abstract: Key Points miRNAs activate NK cells through a TLR–NF-κB signaling pathway and may have therapeutic applications in cancer.

Cited by 77 publications

References 37 publications

The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human NK Cells through Upregulation of TLR-Mediated NF-κB Signaling

The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human NK Cells through Upregulation of TLR-Mediated NF-κB Signaling

TLR7/8 agonists promote NK–DC cross-talk to enhance NK cell anti-tumor effects in hepatocellular carcinoma

PTEN Is a Negative Regulator of NK Cell Cytolytic Function

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