ArticleNucleic acids research2008
Knockdown of TNFR1 by the sense strand of an ICAM-1 siRNA: dissection of an off-target effect.
Article in Nucleic acids research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
20 citing papers in PubMed, 54 citations in OpenAlex.
- Chemical Strategies to Enhance Antisense Strand Selection and Minimize Off-Target Effect-Mediated by siRNAs.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Tumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133FASEB bioAdvances · 2020Article
- Tumor necrosis factor alpha mediates neuromuscular synapse elimination.Cell discovery · 2020Article
- Circular siRNAs for Reducing Off-Target Effects and Enhancing Long-Term Gene Silencing in Cells and Mice.Molecular therapy. Nucleic acids · 2018Article
- Site-Specific Modification Using the 2'-Methoxyethyl Group Improves the Specificity and Activity of siRNAs.Molecular therapy. Nucleic acids · 2017Article
- Blocking sense-strand activity improves potency, safety and specificity of anti-hepatitis B virus short hairpin RNA.EMBO molecular medicine · 2016Article
- Properties of short double-stranded RNAs carrying randomized base pairs: toward better controls for RNAi experiments.RNA (New York, N.Y.) · 2015Article
- Synthesis, physicochemical and biological properties of oligonucleotides incorporated with amino-isonucleosides.Science China. Chemistry · 2012Article
- Non-targeting siRNA induces NPGPx expression to cooperate with exoribonuclease XRN2 for releasing the stress.Nucleic acids research · 2012Article
- Selection and optimization of asymmetric siRNA targeting the human c-MET gene.Molecules and cells · 2011Article
- Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach.Pharmaceuticals (Basel, Switzerland) · 2011Review
- Modified siRNA structure with a single nucleotide bulge overcomes conventional siRNA-mediated off-target silencing.Molecular therapy : the journal of the American Society of Gene Therapy · 2011Article
- Structural diversity repertoire of gene silencing small interfering RNAs.Nucleic acid therapeutics · 2011Review
- A role for human Dicer in pre-RISC loading of siRNAs.Nucleic acids research · 2011Article
- A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects.Nucleic acids research · 2010Article
- Appl1 is dispensable for Akt signaling in vivo and mouse T-cell development.Genesis (New York, N.Y. : 2000) · 2010Article
- siDirect 2.0: updated software for designing functional siRNA with reduced seed-dependent off-target effect.BMC bioinformatics · 2009Article
- High throughput genome-wide survey of small RNAs from the parasitic protists Giardia intestinalis and Trichomonas vaginalis.Genome biology and evolution · 2009Article
- Asymmetric shorter-duplex siRNA structures trigger efficient gene silencing with reduced nonspecific effects.Molecular therapy : the journal of the American Society of Gene Therapy · 2009Article
- Both strands of siRNA have potential to guide posttranscriptional gene silencing in mammalian cells.PloS one · 2009Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Tumor necrosis factor (TNF) initiates local inflammation by triggering endothelial cells (EC) to express adhesion molecules for leukocytes such as intercellular adhesion molecule-1 (ICAM-1 or CD54). A prior study identified siRNA molecules that reduce ICAM-1 expression in cultured human umbilical vein EC (HUVEC). One of these, ISIS 121736, unexpectedly inhibits TNF-mediated up-regulation of additional molecules on EC, including E-selectin (CD62E), VCAM-1 (CD106) and HLA-A,B,C. 736 siRNA transfection was not toxic for EC nor was there any evidence of an interferon response. 736 Transfection of EC blocked multiple early TNF-related signaling events, including activation of NF-kappaB. IL-1 activation of these same pathways was not inhibited. A unifying explanation is that 736 siRNA specifically reduced expression of mRNA encoding tumor necrosis factor receptor 1 (TNFR1) as well as TNFR1 surface expression. A sequence with high identity to the 736 antisense strand (17 of 19 bases) is present within the 3'UTR of human TNFR1 mRNA. An EGFP construct incorporating the 3'UTR of TNFR1 was silenced by 736 siRNA and this effect was lost by mutagenesis of this complementary sequence. Chemical modification and mismatches within the sense strand of 736 also inhibited silencing activity. In summary, an siRNA molecule selected to target ICAM-1 through its antisense strand exhibited broad anti-TNF activities. We show that this off-target effect is mediated by siRNA knockdown of TNFR1 via its sense strand. This may be the first example in which the off-target effect of an siRNA is actually responsible for the anticipated effect by acting to reduce expression of a protein (TNFR1) that normally regulates expression of the intended target (ICAM-1).
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.