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At least 721 records · Page 40Linked to original sources
PubMed2006

Microglia recognize double-stranded RNA via TLR3.

Microglia are CNS resident innate immune cells of myeloid origin that become activated and produce innate proinflammatory molecules upon encountering bacteria or viruses. TLRs are a phylogenetically conserved diverse family of sensors for pathogen-associated molecular patterns that drive innate immune responses. We have recently shown that mice deficient in TLR3 (TLR3(-/-) mice) are resistant to lethal encephalitis and have reduced microglial activation after infection with West Nile virus, a retrovirus that produces dsRNA. We wished to determine whether microglia recognize dsRNA through the TLR3 pathway. In vitro, murine wild-type primary cultured microglia responded to synthetic dsRNA polyinosinic-polycytidylic acid (poly(I:C)) by increasing TLR3 and IFN-beta mRNA and by morphologic activation. Furthermore, wild-type microglia dose dependently secreted TNF-alpha and IL-6 after poly(I:C) challenge, whereas TLR3(-/-) microglia produced diminished cytokines. Activation of MAPK occurred in a time-dependent fashion following poly(I:C) treatment of wild-type microglia, but happened with delayed kinetics in TLR3(-/-) microglia. As an in vivo model of encephalitis, wild-type or TLR3(-/-) mice were injected intracerebroventricularly with poly(I:C) or LPS, and microglial activation was assessed by cell surface marker or phospho-MAPK immunofluorescence. After intracerebroventricular injection of poly(I:C), microgliosis was clearly evident in wild-type mice but was nearly absent in TLR3(-/-) animals. When taken together, our results demonstrate that microglia recognize dsRNA through TLR3 and associated signaling molecules and suggest that these cells are key sensors of dsRNA-producing viruses that may invade the CNS.

Animals↗
PubMed2006

TLR3-involved modulation of pregnancy tolerance in double-stranded RNA-stimulated NOD/SCID mice.

This study aims to extend understanding of the relationship between TLR3-involved cell signaling and dsRNA-induced embryo resorption. Upon stimulation of dsRNA, the resorption rate of embryos was boosted dramatically in syngeneic mating BALB/c mice, but not significantly influenced in syngeneic mating NOD/SCID mice. Accordingly, there was an enhanced cell surface expression of TLR3 on placental CD45(+) cells derived from BALB/c mice, concomitant with both increased percentages of CD45(+)CD80(+) cells and CD8alpha(+)CD80(+) cells in flow cytometric analysis. In addition, both increased IL-2 and decreased IL-10 expression could be observed in CD45(+) cell group in the intracellular detection by flow cytometry. In contrast, no such trends were observed in NOD/SCID model, and its resorption rate of embryos was kept at a low level throughout pregnancy. Neutralizing Abs against TLR3 could abrogate the embryo rejection induced by dsRNA in BALB/c mice, and simultaneously could reduce the CD80(+) percentage in the CD45(+) cell group. These results indicate that the interaction between dsRNA and TLR3 may be involved in the mobilization of CD45(+)CD80(+) and CD8alpha(+)CD80(+) cells, followed by the up-regulation of IL-2 and down-regulation of IL-10 expression at the feto-maternal interface, and finally resulting in embryo rejection. The relatively low responsiveness of NOD/SCID mice may be one of the reasons why these mice appeared to be resistant to dsRNA-induced embryo resorption.

Aging↗
PubMed2006

Innate cytokine responses in porcine macrophage populations: evidence for differential recognition of double-stranded RNA.

Pulmonary airways are vulnerable to infection because of exposure to Ag during respiration. The innate, antiviral response must be activated rapidly after pathogen recognition, and alveolar macrophages (AMphi) play a role in this response. TLR3 and protein kinase R (PKR) recognize dsRNA, a replication intermediate of RNA viruses, and initiate transcription of IFN-alphabeta. In this study, synthetic dsRNA poly(I:C) was used to investigate innate responses of porcine AMphi compared with responses of peritoneal macrophages (PMphi). Poly(I:C) triggered IFN-alphabeta in AMphi and PMphi, but levels in AMphi were higher. In contrast, mRNA levels of IFN-stimulated genes, Mx and PKR, were greater in PMphi than AMphi. Low levels of Mx and PKR transcription in AMphi were not due to deficient type I IFN receptor signaling, as exogenous IFN-alpha induced nuclear translocation of phosphorylated STAT1. To investigate the differential mechanism by which IFN-alphabeta transcription is activated in AMphi and PMphi, 2-aminopurine (2-AP) was used to block dsRNA-mediated activation of PKR. IFN-alphabeta, Mx, and PKR mRNA levels in AMphi after poly(I:C) treatment were unaffected by 2-AP; conversely, transcription of IFN-alphabeta, Mx, or PKR remained at baseline levels in PMphi. Phosphorylated PKR was detected in PMphi, but not AMphi, after poly(I:C) treatment. In addition to IFN-alphabeta gene induction, mRNA levels of TNF-alpha and RANTES were higher in AMphi than PMphi after poly(I:C) stimulation. In summary, differential dsRNA-induced cytokine expression patterns between AMphi and PMphi provide evidence that dsRNA recognition and subsequent signaling is likely mediated via TLR3 in AMphi and PKR in PMphi.

Animals↗
PubMed2003

[RNA interference directed by small hairpin RNA expressed in COS-7 cells].

RNA interference is a phenomenon of gene silencing directed by double-stranded RNA. It can specifically inhibit gene expression by degrading mRNA efficiently and has been widely used to knockdown gene expression in Caenorhabditis elegans, Drosophila melanogaster, etc. For mammalian cells, dsRNA directed RNAi was detected only in murine undifferentiated ES or embryonic carcinoma (EC) cells. Our previous work proved the existence of RNAi effect for reporter gene GFP and endogenous gene Oct4 in undifferentiated murine ES cells. Yet in other kinds of mammalian cells, because of the existence of interferon pathway, long dsRNA will induce the cells to shutdown global protein translation and go to apoptosis. Therefore, dsRNA longer than 30 bp cannot be used to induce specific gene knockdown effect in these cells. Elbashir et al found that in vitro synthesized small interfering RNA (siRNA) (19-23 nt) could induce potent RNAi as effective as long dsRNA without showing unspecific effect, so that the interferon pathway could be bypassed. It was shown that during RNAi process, long dsRNA was first degraded into 19-23 nt siRNA and then recruited into RISC (RNA induced silencing complex) to degrade corresponding mRNA. However, the synthesis of siRNA is expensive and the effect is transient because the knockdown effect can only be maintained for about a week. Recently, it has been shown that U6 promoter directed small hairpin RNA (shRNA) can induce potent gene knockdown effect in murine P19 Embryonic Carcinoma cell. The RNAi effect of U6 promoter-driven shRNA corresponding to Green Fluorescence Protein (GFP) in COS-7 cells was checked. And it was found that the U6 promoter-driven shRNA for GFP can specifically and potently knockdown the GFP's expression in COS-7 cells. The result established the feasibility of using RNAi technique directed by U6 promoter-driven shRNA to study genes' function in COS-7 cell line.

Animals↗
PubMed1992

Oncogenic ras induces an inhibitor of double-stranded RNA-dependent eukaryotic initiation factor 2 alpha-kinase activation.

The interferon-inducible 68-kDa dsRNA-dependent eIF2 alpha-kinase (dsI) is a potent cellular antiviral enzyme which is activated by autophosphorylation in response to double-stranded RNA (dsRNA). Activated dsI has also been implicated as a second messenger for gene induction by platelet-derived growth factor (PDGF) and interferon (IFN). We have shown previously that introduction of a transforming ras gene into BALB/c-3T3 fibroblasts blocks induction of responsive genes by PDGF and IFN. We therefore investigated the effect of transforming ras genes on dsI activity in these cells. We report here that dsRNA-mediated activation of dsI is blocked in v-ras-containing cells in a manner specific to ras and not attributable to the transformed phenotype since: 1) a dexamethasone-inducible v-Ha-ras gene produced the effect within 18 h of induction; 2) morphologic reversion of ras-transformed cells with cAMP or the Krev-1 gene restored potential for dsI activation; and 3) transformation by v-mos or v-abl had no effect on dsI activation. Latent dsI levels were unaffected by v-ras. A heat-sensitive dsI inhibitory activity could be demonstrated in v-ras-containing cells which functioned in trans when mixed with untransformed cell extracts prior to stimulation with dsRNA. The inhibitory activity, which was destroyed by phenol-chloroform extraction, did not bind dsRNA.

3T3 Cells↗
PubMed2004

Inhibition of epidermal growth factor receptor expression by RNA interference in A549 cells.

AIM: To investigate the biological features of A549 cells in which epidermal growth factor (EGF) receptors expression were suppressed by RNA interference (RNAi). METHODS: A549 cells were transfected using short small interfering RNAs (siRNAs) formulated with Lipofectamine 2000. The EGF receptor numbers were determined by Western blotting and flowcytometry. The antiproliferative effects of sequence specific double stranded RNA (dsRNA) were assessed using cell count, colony assay and scratch assay. The chemosensitivity of transfected cells to cisplatin was measured by MTT. RESULTS: Sequence specific dsRNA-EGFR down-regulated EGF receptor expression dramatically. Compared with the control group, dsRNA-EGFR reduced the cell number by 85.0 %, decreased the colonies by 63.3 %, inhibited the migration by 87.2 %, and increased the sensitivity of A549 to cisplatin by four-fold. CONCLUSION: Sequence specific dsRNA-EGFR were capable of suppressing EGF receptor expression, hence significantly inhibiting cellular proliferation and motility, and enhancing chemosensitivity of A549 cells to cisplatin. The successful application of dsRNA-EGFR for inhibition of proliferation in EGF receptor overexpressing cells can help extend the list of available therapeutic modalities in the treatment of non-small-cell lung carcinoma (NSCLC).

Adenocarcinoma↗
PubMed2005

[Antitumor effect of epidermal growth factor receptor gene silencing].

OBJECTIVE: To investigate whether chemically synthesized double-stranded RNA (dsRNA) targeting epidermal growth factor receptor (EGFR) could induce gene silencing in non-small-cell lung cancer (NSCLC) cells, and to assess the degree of EGFR gene silencing and its effect on functional outcome. METHODS: NSCLC cell line SPC-A-1 was transfected with target sequence-specific dsRNA formulated with Lipofectamine 2000. Fluorescent microscopy and flow cytometry were used to measure the reduction in the production of the EGFR protein. Real-time PCR was used to detect the silencing of the EGFR gene level. Colony assay was adopted to measure the cellular proliferation and colony formation. A tumor burdened athymic nude mouse model was established to calculate the tumor growth inhibition rate. RESULTS: The dsRNA-EGFR was shown to be effective with a 71.3% down-regulation of EGFR protein production and 50.0% of silencing of EGFR gene. The dsRNA-EGFR significantly reduced colony numbers by 66.8% in vitro and inhibited the tumor growth in vivo. The tumor growth inhibition rate was 75.0%. CONCLUSION: The sequence specific dsRNA showed a blockbuster effect in downregulation of EGFR gene level and protein production, inhibition of the cellular proliferation and tumor growth.

Animals↗
PubMedDate not supplied

[Compact form of DNA in solution. XII. Double-stranded polyribonucleotide compacting in the presence of polyethylene glycol].

Double-stranded polyribonucleotides (a replicative form of phage f2 RNA--dsRNA and poly(A) poly(U), can adopt a compact from in solutions, containing NaCl and poly(ethylene glycol) (PEG). According to electron-microscopic observations dsRNA compact particles have the form of disks or doughnuts 200--400 A in diameter. X-ray diffraction patterns from dense slurries of dsRNA compact particles show a reflection at a spacing of 35 A, which is indicative of the existance of ordered regions in compact particles. The intense positive CD band, which is characteristic of dsRNA and poly(A) poly(U) compact particles, presumably results from the ordered regions in the particles. Heating of the solution leads to the disappearance of the intense positive CD band, probably as a result of the destruction of the ordered structure of compact particles. Heat or acid denatured dsRNA molecules as well as single-stranded molecules of ribosomal RNA also form large particles in PEG-containing solutions. However, X-ray diffraction patterns from these particles do not show the 35 A reflection and the specific positive band is not present in their CD spectra, which indicates that such particles lack ordered internal structure. It is suggested that similar mechanism of compactization of double-stranded polynucleotides (DNA and RNA) exist, and compact particles may be divided into two families (psi+ and psi-), differing by the secondary structure of double-stranded polynucleotides, which form the particles.

Bacteriophages↗
PubMed1983

Phosphorylation of initiation factor eIF-2 alpha, binding of mRNA to 48 S complexes, and its reutilization in initiation of protein synthesis.

The formation of 80 S initiation complexes containing labeled viral mRNA was drastically inhibited when mRNA binding assays were carried out with reticulocyte lysate preincubated with double-stranded RNA (dsRNA). When the assays were analyzed by centrifugation on sucrose gradients, the mRNA incubated with lysate pretreated with dsRNA sedimented as a 48 S complex. Met-tRNA, GDP, and phosphorylated initiation factor eIF-2(alpha P) were shown to co-sediment with the 48 S complex. Therefore, the formation of this complex was attributed to the phosphorylation of eIF-2 alpha by a dsRNA-activated protein kinase. These observations suggested that mRNA could bind to a 40 S ribosomal subunit containing Met-tRNAf, GDP, and eIF-2(alpha P), but the joining of a 60 S ribosomal subunit was inhibited. When the 48 S complex was isolated and incubated with lysate without added dsRNA, the mRNA could form 80 S initiation complexes. The shift of mRNA from 48 S to 80 S complexes was also observed when the eIF-2 alpha kinase activity was inhibited by the addition of 2-aminopurine. This shift was quite slow, however, when compared to the rate of binding of free mRNA to 80 S initiation complexes. The 2-aminopurine was effective in reversing the inhibition of protein synthesis by dsRNA and in maintaining a linear rate of protein synthesis for 3 h in lysates. Without added 2-aminopurine, protein synthesis was inhibited after 90 min even in lysates supplemented with hemin and eIF-2(alpha P) was detected in these lysates. This finding indicated that eIF-2 alpha phosphorylation could be in part responsible for limiting the duration of protein synthesis in mammalian cell-free systems.

Adenosine Triphosphate↗
PubMed1994

Role of the amino-terminal residues of the interferon-induced protein kinase in its activation by double-stranded RNA and heparin.

We have previously reported that the amino-terminal residues 1-34 of the interferon-induced protein kinase (RNA-activated) (PKR) are necessary for its binding to and activation by double-stranded RNA (dsRNA) (Patel, R. C., and Sen, G. C. (1992) J. Biol. Chem. 267, 7671-7676). Here, we report that the amino-terminal 24 residues are indispensable for these properties of the enzyme. The replacement of these residues with 14 unrelated residues fully restored the protein's dsRNA binding activity, but only partially restored the enzyme activity. Mutation of residues 18 and 19 revealed their importance in determining the affinity of PKR for dsRNA and its ability to phosphorylate eukaryotic initiation factor 2 alpha. These mutations, however, did not affect PKR's autophosphorylation activity. Deletion mutants that failed to bind to and be activated by dsRNA could be fully activated by the alternative activator, heparin. Thus, activation of PKR by dsRNA and heparin is mediated through different mechanisms that require different domains of the protein.

Amino Acid Sequence↗
PubMed1996

Detection of double-stranded RNA-protein interactions by methylene blue-mediated photo-crosslinking.

Double-stranded(ds) RNA-binding proteins have diverse functions in the cell. An obstacle to investigating the interactions between these proteins and dsRNA is the relative inefficiency of traditional UV-crosslinking methods for extended regions of dsRNA. We have therefore developed an alternative procedure for RNA-protein photo-crosslinking that efficiently induces RNA-protein crosslinks in double-stranded regions of RNA. We show that dsRNA-protein crosslinks can be induced by visible light in the presence of the dye methylene blue, which most likely mediates crosslinking by intercalating in the dsRNA helix. A recombinant dsRNA binding domain from the Drosophila staufen protein and human protein kinase R were crosslinked by UV or methylene blue to a series of dsRNAs. In each case, the degree of crosslinking was greater with methylene blue, particularly with RNAs with few single-stranded loops. Methylene blue-mediated crosslinking therefore complements and extends the existing repertoire of crosslinking methods for detecting RNA-protein interactions.

Animals↗
PubMed1996

Loss ability to produce IFN-alpha in response to HIV-1 as monocytes differentiate into macrophages. Induction through a mechanism independent of double-stranded RNA.

IFN-alpha is an antiviral cytokine detected in plasma of HIV-1-infected patients during acute viremia and during late-stage disease. Monocytes produced IFN-alpha in response to HIV-1:1) IFN-alpha was produced predominantly by adherent cells; 2) depleting CD14+ cells nearly abolished HIV-1-induced IFN-alpha production; and 3) intracytoplasmic IFN-alpha was detected in CD14+ cells. During cell culture, monocytes differentiated into macrophages and lost their ability to produce IFN-alpha when challenged with HIV-1. These cells remained capable of producing IFN-alpha in response to other stimuli such as poly(I:C), a synthetic dsRNA. Thus, we examined two negative-stranded RNA viruses that have dsRNA intermediates, Newcastle disease virus and Sendai virus, and a DNA virus, herpes simplex virus type I (HSV-1). Macrophages lost their ability to produce IFN-alpha in response to HSV-1, but not to Sendai virus or to Newcastle disease virus. Thus, HIV-1 and other viruses were capable of inducing IFN-alpha through a mechanism that was independent of dsRNA. In conclusion, these data suggest that there are dsRNA-dependent and -independent mechanisms for the induction of IFN-alpha production, and that as monocytes differentiate into macrophages, they selectively lose their ability to produce IFN-alpha through the dsRNA-independent mechanism.

Cell Differentiation↗
PubMed2026

Cold-adapted RNA polymerase from Pseudomonas phage Njord improves synthesis of therapeutic mRNA.

An RNA polymerase identified in the genome of Pseudomonas phage Njord offers a promising tool for the synthesis of mRNA and other therapeutic nucleic acids. Originating from a marine microbial ecosystem, Njord RNAP transcribes RNA at high yield even under low temperature conditions. Key properties of the enzyme relevant to mRNA synthesis are presented including transcriptional fidelity, promoter specificity, incorporation of modified nucleotides, and the impurity profile of the RNA. Specific attention is given to the formation of contaminating double-stranded RNA (dsRNA) species. Analysis of transcription reactions shows that DNA-templated promoter-independent transcription is a major source of detectable dsRNA impurities and that Njord RNAP displays a minimal level of this activity. Consistent with the known inflammatory role of dsRNA in synthetic mRNA, transcriptomic analysis of cell culture and a live animal study demonstrates that mRNA synthesized with Njord RNAP elicits only a minimal immune response. This natural enzyme enables efficient mRNA synthesis at ambient temperature and produces transcripts essentially free of dsRNA, offering significant potential to streamline mRNA manufacturing processes.

DNA-Directed RNA Polymerases↗
PubMed1989

Internal and terminal cis-acting sites are necessary for in vitro replication of the L-A double-stranded RNA virus of yeast.

Empty particles of the L-A dsRNA virus of Saccharomyces cerevisiae bind to added viral (+) strands and convert them to dsRNA (RNA replication) in an in vitro reaction that is dependent on host factors. X dsRNA (530 bp long) is a deletion derivative of L-A dsRNA (4.5 kb). By modifying our cDNA clone of X and testing template activity of T7 RNA polymerase transcripts, we have found that both the 3' end 30 bases and an internal site on the (+) strand are necessary for optimal replication [in vitro (-) strand synthesis]. Changing any one of the 3' terminal three bases eliminates template activity, but the 3' terminal five bases of M1 (a satellite virus of L-A) can replace the 3' terminal four bases of X. A subterminal stem-loop structure is also important for template activity. The internal site that enhances replication is approximately 400 bp from the 3' end and is distinct from the site necessary for binding of (+) strands to the empty viral particles.

Base Sequence↗
PubMed1989

Double-stranded RNA activates binding of NF-kappa B to an inducible element in the human beta-interferon promoter.

The human beta-interferon promoter contains at least two positive acting domains (PRD I and PRD II). PRD I has been previously shown to stimulate basal transcription and to respond to induction by double-stranded RNA (dsRNA). Here we show that PRD II functions independently as a constitutive element that also responds to induction. A cellular factor that specifically binds to PRD II has been identified, and the levels of this factor increase markedly in extracts from cells treated with dsRNA. The inducible factor has a binding specificity that is indistinguishable from the transcription factor NF-kappa B. As has been shown for NF-kappa B, the PRD II-specific factor can be activated in uninduced extracts by treatment with detergent, suggesting that the inactive state is due to association with an inhibitory factor. Induction by dsRNA therefore provides a novel means for the post-translational activation of NF-kappa B. Potential binding sites for NF-kappa B are present in the 5' flanking regions of a number of genes involved in the immune response, several of which are inducible by dsRNA. These findings demonstrate a role for NF-kappa B in the physiological activation of genes in non-lymphoid cells.

Animals↗
PubMed2026

Comparative evaluation of chitosan-based and star polycation nanocarriers for enhanced RNAi efficacy targeting CmFibL in Cnaphalocrocis medinalis.

BACKGROUND: The rice leaf folder, Cnaphalocrocis medinalis, causes substantial rice yield losses through larval leaf-rolling behavior. RNA interference (RNAi) offers a sustainable alternative, but its application in Lepidoptera is hindered by dsRNA degradation and poor cellular uptake. This study developed nanocarrier-mediated dsRNA delivery to overcome these limitations. RESULTS: Three nanocarriers - chitosan (CS), chitosan-tripolyphosphate (CS-TPP), and star polycation (SPc) - were compared for enhancing RNAi efficiency targeting the C. medinalis fibroin light chain gene (CmFibL). CS-TPP and SPc achieved 61% and 55% silencing efficiency, respectively, representing 2.7-fold improvement over naked dsRNA (23%). All nanocarriers protected dsRNA from RNase A (30 min) and midgut fluid (6 h) degradation. CmFibL knockdown caused severe silk defects, prolonged pupal duration by 23%, reduced pupal weight by 33%, and decreased leaf-rolling damage by 31% in glasshouse cage trials. Transcriptomics revealed down-regulation of amino acid metabolism and activation of endoplasmic reticulum (ER) stress and immune responses. No off-target effects were detected in human genome, nor in any predators or parasitoids sharing the same ecological niche. CONCLUSION: CS-TPP and SPc nanocarriers effectively enhance RNAi efficiency in a Lepidopteran pest. Targeting CmFibL disrupts silk-mediated feeding shelters with minimal ecological risk, providing a practical framework for field application of RNAi-based biopesticides against leaf-rolling rice pests. © 2026 Society of Chemical Industry.

Animals↗
PubMed2000

RNA interference for the organizer-specific gene Xlim-1 in Xenopus embryos.

Double-stranded RNA (dsRNA) interferes with gene expression in various species, a phenomenon known as RNA interference (RNAi). We show here that RNAi is also effective in modifying gene expression in Xenopus embryos. First, expression of an exogenous luciferase gene as a reporter in embryos was reduced by coinjection with dsRNA corresponding to the luciferase gene. Next, injection of dsRNA for Xlim-1, a homeobox gene suggested to be involved in Spemann organizer functions, reduced the endogenous level of Xlim-1 mRNA and produced embryos with reduced eyes or anterior truncation at high efficiency. In addition, injection of an antisense expression construct of Xlim-1 elicited phenotypes very similar to those of Xlim-1 dsRNA-injected embryos. These results indicate the effectiveness of RNAi for loss of function studies in Xenopus embryos, and the importance of Xlim-1 in head formation.

Animals↗
PubMed1999

The importance of internal loops within RNA substrates of ADAR1.

Adenosine deaminases that act on RNA (ADARs) are a family of RNA editing enzymes that convert adenosines to inosines within double-stranded RNA (dsRNA). Although ADARs deaminate perfectly base-paired dsRNA promiscuously, deamination is limited to a few, selected adenosines within dsRNA containing mismatches, bulges and internal loops. As a first step in understanding how RNA structural features promote selectivity, we investigated the role of internal loops within ADAR substrates. We observed that a dsRNA helix is deaminated at the same sites whether it exists as a free molecule or is flanked by internal loops. Thus, internal loops delineate helix ends for ADAR1. Since ADAR1 deaminates short RNAs at fewer adenosines than long RNAs, loops decrease the number of deaminations within an RNA by dividing a long RNA into shorter substrates. For a series of symmetric internal loops related in sequence, larger loops (>/=six nucleotides) acted as helix ends, whereas smaller loops (</=four nucleotides) did not. Our work provides the first information about how secondary structure within ADAR substrates dictates selectivity, and suggests a rational approach for delineating minimal substrates for RNAs deaminated by ADARs in vivo.

Adenosine Deaminase↗