Sequence determinants of innate immune activation by short interfering RNAs

Goodchild, Amber; Nopper, Nicole; King, Andrew; Doan, Tram; Tanudji, Marcel; Arndt, Greg M.; Poidinger, Michael; Rivory, Laurent P.; Passioura, Toby

doi:10.1186/1471-2172-10-40

Cited by 59 publications

(48 citation statements)

References 40 publications

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“…Therefore, the effects that we may observe are oftentimes indirect and result from long term alterations in gene expression. Secondly, small interfering RNA are recognized by the Toll-like receptor 8 and retinoic acid-inducible protein 1 that are present in monocytes (53). This recognition triggers downstream signaling via Tollinterleukin-1 receptor domains activating the interferon regulatory factor, nuclear factor -light chain enhancer of activated B cells and MAPK pathways leading to the expression of interferon, proinflammatory cytokines, as well as IL-10 (54).…”

Section: Discussionmentioning

confidence: 99%

Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Wong

Campbell

Spector

2010

Journal of Biological Chemistry

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The clade B human immunodeficiency virus, type 1 (HIV-1) Tat (trans-acting regulatory protein) induces interleukin-10 (IL-10) production in monocytes. IL-10, an anti-inflammatory cytokine, down-regulates proinflammatory cytokines and suppresses the immune response, leading to a rapid progression from HIV-1 infection to AIDS. Nine clades of HIV-1 are responsible for the majority of infections worldwide. Recent studies demonstrate that different HIV-1 clades have biological differences in relation to transmission, replication, and disease progression. In this study, we show that the cysteine to serine mutation at position 31, found in >90% of HIV-1 clade C Tat proteins, results in a marked decrease in IL-10 production in monocytes compared with clade B Tat. Additionally, the C31S mutation found in C Tat is responsible for the inability of these Tat proteins to produce high IL-10 levels in monocytes due to its inability to induce intracellular calcium flux through L-type calcium channels. Moreover, we show that p38␣/p38␤ and phosphoinositide 3-kinase are crucial to Tat-induced IL-10 production. These findings provide further evidence that HIV-1 clades differ in their biological properties that may impact HIV-1 pathogenesis and disease progression.The human immunodeficiency virus type 1 (HIV-1) 3 transacting regulatory protein (Tat) is an 86 -101-residue protein involved in initiating viral transcription and RNA chain elongation. In addition to its primary role as a transcriptional activator of viral gene expression, Tat is actively released from unruptured, HIV-1-infected cells and is detectable in ex vivo culture supernatants and in the serum of HIV-1 infected individuals (1, 2). Most exogenous Tat studies use a truncated 86-residue HIV-1 clade B Tat with few studies examining the functions of other clades or isotypes (3). However, these studies have shown that exogenous B Tat induces the production of cytokines, such as tumor necrosis factor, chemokine (C-C motif) ligand 2 (CCL2), interleukin-6 (IL-6), and interleukin-10 (IL-10) from monocytes and macrophages (4 -9).The expression of IL-10-specific mRNA and the production of IL-10 are both increased in HIV-1-infected individuals (10 -12). IL-10 is an anti-inflammatory cytokine produced by a wide variety of cells including monocytes, macrophages, T cells, natural killer cells, and B cells (13) that down-regulates major histocompatibility complex class II (13) and inhibits T cell proliferation while reducing the production of proinflammatory cytokines. Elevated IL-10 levels are found in individuals with rapid progression to AIDS (14 -16), and individuals with higher plasma levels of IL-10 have more severely compromised T helper cell function (14 -16) combined with lower T helper cell counts (17). Interestingly, in samples from patients chronically infected with HIV, blocking the IL-10/IL-10 receptor pathway in vitro using specific antibodies enhanced CD4 ϩ T cell responses (14 -16). Therefore, maintaining low levels of IL-10 may slow HIV-1 disease progression.Recen...

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Section: Discussionmentioning

confidence: 99%

Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Wong

Campbell

Spector

2010

Journal of Biological Chemistry

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“…This results in the detection of a greater variety of small RNAs ( 16,18 ) . In addition to speci fi c uridine motifs, we and others have recently proposed that the af fi nity between the two complementary strands of an siRNA could in fl uence recruitment of TLR7/8 in human immune cells ( 19,20 ) . Making use of this observation, we characterized an siRNA scaffold allowing for increased TLR7/8 activation while retaining full RNAi ef fi cacy ( 19 ) .…”

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confidence: 99%

Strategies for Designing and Validating Immunostimulatory siRNAs

Gantier

2012

Methods in Molecular Biology

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Specific clinical applications of RNA interference (RNAi) can benefit from a concurrent activation of the immune system. This is the case for small interfering RNAs (siRNAs) with antitumor or antiviral activities. This chapter provides a brief overview of the strategies reported to date to design siRNAs with gene silencing and immune activating properties, as well as methods for the validation of immunostimulatory activities.

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“…Goodchild et al demonstrated a model of TLR7/8 activation by siRNAs, in which the two strands are denatured in the endosome, and single-stranded, U-rich RNA species activate TLR7/8 [36] . A follow-up study is warranted to determine whether these highly specific RNA species already identified are also useful in the development of pharmacological agents with cardioprotective applications.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 7/8 agonist resiquimod induces late preconditioning in neonatal cardiac myocytes

et al. 2011

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Aim: To investigate whether R-848 (resiquimod, toll-like receptor 7/8 agonist) can induce late preconditioning in neonatal cardiac myocytes. Methods:The protective effects of R-848 on neonatal myocytes against anoxia-reoxygenation-induced injury were tested, and intracellular reactive oxygen species (ROS) were determined. The protein synthesis inhibitor cyclohexamide (CH) and the ROS scavenger N-acetylcysteine (NAC) were used in this model to test if new protein synthesis and oxidative stress were necessary for their cardioprotective effects. The activation of nuclear factor kappa B (NFκB) and hypoxia inducible factor 1 (HIF1) was investigated by electrophoretic mobility shift assays (EMSA), and inducible nitric oxide synthase (iNOS) was assessed by immunoblotting. After iNOS was downregulated by small interfering RNA (siRNA) transfection, the cardioprotective effect was reassessed. Results: ROS were triggered soon after R-848 (0.01-1.0 μg/L) administration, however, the cardioprotective effect of which was induced 24 h later. This protection was abolished by CH or NAC pretreatment. NFκB and HIF1 activation and iNOS up-regulation were involved in this protective mechanism. The cardioprotective effect was also attenuated after iNOS was knocked down. Conclusion: R-848 provided a cardioprotective effect through a late preconditioning mechanism via a ROS/NFκB-HIF1/iNOS-dependent pathway.

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Sequence determinants of innate immune activation by short interfering RNAs

Cited by 59 publications

References 40 publications

Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Strategies for Designing and Validating Immunostimulatory siRNAs

Toll-like receptor 7/8 agonist resiquimod induces late preconditioning in neonatal cardiac myocytes

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