Induction of an interferon response by RNAi vectors in mammalian cells

Bridge, Alan; Pébernard, Stéphanie; Ducraux, Annick; Nicoulaz, Anne-Laure; Iggo, Richard

doi:10.1038/ng1173

Cited by 879 publications

(651 citation statements)

References 6 publications

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“…Interferon induction was attributed to the initiating triphosphates on the siRNA resulting from the bacteriophage promoters. In another study, several siRNAs incorporated into lentiviruses or plasmids did induce interferon, 32 but similar to the report of Rossi et al, chemically synthesized siRNA did not. Furthermore, in this study it was noted that when siRNA was incorporated into expression vectors, the H3 RNA polymerase promoter induced less interferon than did the U6 promoter.…”

Section: Raf-1 Inhibits Tumor Growth Q Leng and Aj Mixsonsupporting

confidence: 66%

“…Nevertheless, there have been few recent reports challenging the viewpoint that siRNA do not induce cytokines. [32][33][34][35] Rossi et al found that siRNA synthesized by T3, T7, or SP6 bacteriophage polymerase strongly induced interferon a and b in a number of cell lines. 33 In contrast, chemically synthesized siRNA did not induce any interferon response in these cell lines.…”

Section: Raf-1 Inhibits Tumor Growth Q Leng and Aj Mixsonmentioning

confidence: 99%

“…Furthermore, in this study it was noted that when siRNA was incorporated into expression vectors, the H3 RNA polymerase promoter induced less interferon than did the U6 promoter. 32 These reports suggest caution in assuming that siRNA downregulation of its targeted genes is solely sequence-specific. Nevertheless, the vast majority of reports have shown that at least chemically synthesized siRNA do not induce interferon and are sequence-specific in targeting genes.…”

Section: Raf-1 Inhibits Tumor Growth Q Leng and Aj Mixsonmentioning

confidence: 99%

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Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo

Leng

Mixson

2005

Cancer Gene Ther

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Raf-1 is a cytosolic serine-threonine kinase that plays an important role in tumor cell growth, proliferation, and apoptosis. Upregulated Raf-1 activity has also been implicated in tumor angiogenesis and metastasis. In this study, we used a promising new RNA interfering technology that targets Raf-1 mRNA both in vitro and in vivo. We initially found that Raf-1 siRNA markedly reduced Raf-1 mRNA in MDA-MB-435 cells in vitro by approximately 75% compared to control siRNA treatment groups. Raf-1 siRNA also reduced cell number by inducing apoptosis in a number of cell lines including HUVEC, MDA-MB-435, and C6 cells. After screening several histidine-lysine polymers in complex with Raf-1 siRNA to reduce tumor growth, we further evaluated the efficacy of this siRNA in complex with the optimal histidine-lysine carrier to reduce the tumor growth in vivo. MDA-MB-435 xenografts treated by intratumoral injections of Raf-1 siRNA were significantly reduced compared with the control groups. By the fourth measurement, tumor growth was reduced by nearly 60% in the Raf-1 siRNA treatment group compared with the untreated group (Po.02). Taken together, our data provide evidence that Raf-1 siRNA may be an effective strategy for reducing tumor growth.

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Section: Raf-1 Inhibits Tumor Growth Q Leng and Aj Mixsonsupporting

confidence: 66%

Section: Raf-1 Inhibits Tumor Growth Q Leng and Aj Mixsonmentioning

confidence: 99%

Section: Raf-1 Inhibits Tumor Growth Q Leng and Aj Mixsonmentioning

confidence: 99%

See 1 more Smart Citation

Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo

Leng

Mixson

2005

Cancer Gene Ther

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“…Recently, some synthetic siRNAs or shRNA expression vectors were reported to induce interferon responses. 14,15 This is of critical importance in exploring RNAi for clinical application. However, we did not observe the increase of apoptotic cells nor induction of nonspecific gene inhibition in siRNA-or shRNA-treated MCs in vitro or in vivo glomeruli in vivo.…”

Section: Discussionmentioning

confidence: 99%

Exploring RNA interference as a therapeutic strategy for renal disease

et al. 2005

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The short synthetic interfering RNA duplexes (siRNAs) can selectively suppress gene expression in somatic mammalian cells without nonselective toxic effects of double-stranded RNA (dsRNA). However, a selective in vivo delivery of siRNA transfer has not been reported in kidney. Here, we investigated whether injection of synthetic siRNAs via renal artery followed by electroporation could be effective and therapeutic in silencing specific gene in glomerulus. We investigated the effect of siRNA in rat cultured mesangial cells (MCs) and showed that siRNA sequence-specific suppression of transgene expression was over a 1000-fold more potent than that by antisense oligodeoxynucleotide (ASODN). Transfection of siRNA targeting luciferase into rat kidneys significantly inhibited expression of a cotransfected luciferase expression vector in vivo. The delivery of siRNA targeting enhanced green fluorescent protein (EGFP) in the transgenic 'green' rat reduced endogenous EGFP expression, mainly in glomerular MCs. Furthermore, RNAi targeting against TGF-b1 significantly suppressed TGF-b1 mRNA and protein expression, thereby ameliorated the progression of matrix expansion in experimental glomerulonephritis. In addition, vector-based RNAi also inhibited TGF-b1 expression in vitro and in vivo. In conclusion, siRNA-directed TGFb1 silencing may be of therapeutic value in the prevention and treatment of fibrotic diseases. Gene Therapy (2005) 12, 965-973.

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“…In some instances, transfection of retroviral or plasmid vectors producing micro RNA could induce an interferon-like response with the activation of specific genes and nonspecific decrease in translation activity. 34 To rule out this possibility, we monitored the levels of expression of the interferon-induced oligoadenylate synthase 1 (OAS1) gene 35 (Figure 2c). In summary, there was not a significant compensatory increase of IGF2 proteins in IGFBP-5-interfered clones.…”

Section: Generation Of Igfbp-5-interfered Nb Cells By Micro Rnamentioning

confidence: 99%

Silencing of endogenous IGFBP-5 by micro RNA interference affects proliferation, apoptosis and differentiation of neuroblastoma cells

et al. 2004

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Signal transduction through the IGF axis is implicated in proliferation, differentiation and survival during development and adult life. The IGF axis includes the IGF binding proteins (IGFBPs) that bind IGFs with high affinity and modulate their activity. In neuroblastoma (NB), a malignant childhood tumor, we found that IGFBP-5 is frequently expressed. Since NB is an IGF2-sensitive tumor, we investigated the relevance and the function of endogenous IGFBP-5 in LAN-5 and in SY5Y(N) cell lines transfected with micro and small interfering RNAs directed to IGFBP-5 mRNA. Cells in which IGFBP-5 expression was suppressed were growth-inhibited and more prone to apoptosis than the parental cell line and controls. Apoptosis was further enhanced by X-ray irradiation. The ability of these cells to undergo neuronal differentiation was impaired after IGFBP-5 inhibition but the effect was reversed by exposure to recombinant IGFBP-5. Together, these data demonstrate the importance of IGFBP-5 for NB cell functions and suggest that IGFBP-5 might serve as a novel therapeutic target in NB.

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Induction of an interferon response by RNAi vectors in mammalian cells

Cited by 879 publications

References 6 publications

Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo

Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo

Exploring RNA interference as a therapeutic strategy for renal disease

Silencing of endogenous IGFBP-5 by micro RNA interference affects proliferation, apoptosis and differentiation of neuroblastoma cells

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