Journal
BLOOD
Volume 121, Issue 23, Pages 4663-4671Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-07-441360
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Funding
- National Cancer Institute [CA155521, CA095426, CA068458]
- National Blood Foundation
- American Cancer Society [IRG-67-003-47]
- Ohio State University Comprehensive Cancer Center Pelotonia grant
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MicroRNAs (miRNAs) bind to complementary sequences of target mRNAs, resulting in translational repression or target degradation and thus gene silencing. miRNAs are abundant in circulating blood, yet it is not known whether, as a class of regulatory molecules, they interact with human natural killer (NK) cells. Here we found that the treatment of human NK cells with several mature miRNAs in the presence of a low concentration of interleukin-12 induced CD69 expression, interferon-gamma production, and degranulation marker CD107a expression. In vivo, infusion of several miRNAs alone in murine peripheral blood also resulted in comparable NK-cell activation, but not T-cell activation. Furthermore, miRNA administration significantly protected mice from tumor development in an NK cell-dependent manner. Mechanistically, we found that miRNA stimulation led to downstream activation of nuclear factor kappa B (NF-kappa B), an effect that was blunted by a block in Toll-like receptor 1(TLR1) signaling and attenuated in lymphoma patients. Knockdown of TLR1 resulted in less activation by miRNAs. Collectively, we show that miRNAs have a capacity to selectively activate innate immune effector cells that is, at least in part, via the TLR1-NF-kappa B signaling pathway. This may be important in the normal host defense against infection and/or malignant transformation.
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