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* Centre for Cancer Research, Monash Institute of Medical Research; and
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia;
Integrated DNA Technologies, Coralville, IA 52241; and
Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences, Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia
Human TLR7 and 8 (hTLR7/8) have been implicated in the sequence-dependent detection of RNA oligonucleotides in immune cells. Although hTLR7 sequence-specific sensing of short RNAs has been inferred from studies of murine TLR7, this has yet to be established for hTLR7. We found that different short ssRNA sequences selectively induced either TNF-
or IFN- in human PBMCs. The sequence-specific TNF- response to ssRNAs observed in PBMCs could be replicated in activated human macrophage-like (THP-1) cells pretreated with IFN-
. Surprisingly, suppression of hTLR7 expression by RNA interference in this model reduced sensing of all immunostimulatory ssRNAs tested. Modulation of the relative expression ratio of hTLR7 to hTLR8 in THP-1 cells correlated with differential sensing of immunostimulatory sequences. Furthermore, the sequence-specific IFN- induction profile in human PBMCs was accurately modeled by a sequence-specific activation of murine TLR7 in mouse macrophages. Thus, we demonstrate for the first time that hTLR7 is involved in sequence-specific sensing of ssRNAs. We establish a novel cell model for the prediction of TNF- induction by short RNAs in human macrophages. Our results suggest that differential sequence-specific sensing of RNA oligonucleotides between human and mouse macrophages is due to the modulation of TLR7 sensing by human TLR8.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants RO1 A134039 and PO1 CA62220 (to B.R.G.W.).
2 Address correspondence and reprint requests to Prof. Bryan R. G. Williams, Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail address: bryan.williams{at}med.monash.edu.au
3 Abbreviations used in this paper: hTLR7/8, human TLR7/8; pDC, plasmacytoid dendritic cell; mTLR7/8, mouse TLR7/8; siRNA, small interfering RNA; BMM, bone marrow macrophage; DOTAP, N-[1-(2,3-Dioleoyloxy)propyl]-N,N,Ntrimethylammonium methylsulfate.
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