title: MicroRNAs activate natural killer cells through Toll-like receptor signaling.
abstract: 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-γ 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 κB (NF-κB), 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-κB signaling pathway. This may be important in the normal host defense against infection and/or malignant transformation.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: He
authors.forename: Jianhong
authors.initials: J
authors.lastname: Chu
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Alvarez-Breckenridge
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hughes
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.forename: Shunzong
authors.initials: S
authors.lastname: Yuan
authors.forename: Sumeet
authors.initials: S
authors.lastname: Sandhu
authors.forename: Sumithira
authors.initials: S
authors.lastname: Vasu
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.forename: Xiaoming
authors.initials: X
authors.lastname: He
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1; D035683:MicroRNAs; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma