Opposing roles of RNA receptors TLR3 and RIG-I in the inflammatory response to double-stranded RNA in a Kaposi’s sarcoma cell line

Livengood, April J.; Wu, Christina; Carson, Dennis A.

doi:10.1016/j.cellimm.2007.11.004

Cited by 15 publications

(10 citation statements)

References 31 publications

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“…Upon treatment of cells with viral dsRNA, a low level of RIG-I activation increases host cell survival, whereas a higher level of RIG-I activation leads to cell apoptosis [ 22 ]. Furthermore, opposing roles of RNA receptors TLR3 and RIG-I in the inflammatory response to dsRNA has also been shown in a Kaposi's sarcoma cell line SLK [ 23 ]. While TLR3 mediated inflammatory response to poly(I:C), siRIG-I resulted in enhanced chemokine release, in a TLR3 pathway-dependent manner [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, opposing roles of RNA receptors TLR3 and RIG-I in the inflammatory response to dsRNA has also been shown in a Kaposi's sarcoma cell line SLK [ 23 ]. While TLR3 mediated inflammatory response to poly(I:C), siRIG-I resulted in enhanced chemokine release, in a TLR3 pathway-dependent manner [ 23 ]. The role of RIG-I in our NB model may be similar to that in SLK.…”

Section: Discussionmentioning

confidence: 99%

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MDA5 complements TLR3 in suppression of neuroblastoma

et al. 2015

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Toll-like receptor3 (TLR3) has been confirmed to be differentially expressed in neuroblastoma (NB), and predicts a favorable prognosis with a high expression in tumor tissues. Treatment with TLR3 agonist - polyinosinic-polycytidylic acid [poly(I:C)] could induce significant but limited apoptosis in TLR3-expressing NB cells, suggesting that other viral RNA sensors, including melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I) in the cytosolic compartment might also be implicated in poly(I:C)-induced NB cell death. MDA5 and RIG-I were induced by poly(I:C) to express in two of six NB cell lines, SK-N-AS (AS) and SK-N-FI, which were associated with up-regulation of caspase9 and active caspase3. While knockdown of either MDA5 or RIG-I alone is ineffective to decrease caspase9 and active caspase3, simultaneously targeting MDA5 and TLR3 showed the best effect to rescue poly(I:C) induced up-regulation of mitochondrial antiviral signaling protein (MAVS), caspase9, active caspase3, and apoptosis in AS cells. Over-expression of MDA5 in FaDu cells resulted in significantly less colony formation and more poly(I:C)-induced cell death. Further studies in human NB tissue samples revealed that MDA5 expression in NB tissues predicted a favorable prognosis synergistically with TLR3. Our findings indicate that MDA5 may serve as a complementary role in the TLR3 activated suppression of NB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MDA5 complements TLR3 in suppression of neuroblastoma

et al. 2015

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“…The concept of various dsRNA receptors playing selective roles in response to different lengths of synthetic dsRNA and to different types of dsRNA viruses is well established (7, 8). Unfortunately, satisfactory knockdown of IFN-γ-induced RIG-I could not be achieved in our system, although RIG-I sensing of dsRNA may inhibit inflammatory responses in certain cell types (27). Our studies were not an exhaustive analysis of dsRNA sensors, such as protein kinase R and the cryopyrin/Nalp3 inflammasome (28, 29).…”

Section: Discussionmentioning

confidence: 99%

IFN-γ Primes Intact Human Coronary Arteries and Cultured Coronary Smooth Muscle Cells to Double-Stranded RNA- and Self-RNA–Induced Inflammatory Responses by Upregulating TLR3 and Melanoma Differentiation-Associated Gene 5

Ahmad

Ali²,

Lebastchi³

et al. 2010

The Journal of Immunology

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Atherosclerosis of native coronary arteries and graft arteriosclerosis in transplanted hearts are characterized by activation of innate and adaptive immune responses. Nucleic acids generated by infections or cell death have been detected within arteriosclerotic lesions, and it is known that microbial and synthetic nucleic acids evoke inflammatory responses in cultured vascular cells. In this study, we report that model RNA, but not DNA, instigated robust cytokine and chemokine production from intact human coronary arteries containing both intrinsic vascular cells and resident/infiltrating leukocytes. An ssRNA analog induced TNF-α and IFN-γ–induced protein of 10 kDa secretion by isolated human PBMCs, but not vascular cells. Conversely, synthetic dsRNA induced these inflammatory mediators by vascular cells, but not PBMCs. IFN-γ, a cytokine linked to atherosclerosis and graft arteriosclerosis, potentiated the inflammatory responses of intact arteries and cultured vascular smooth muscle cells (VSMCs) to polyinosinic:polycytidylic acid [poly(I:C)] and was necessary for inflammatory responses of VSMC to self-RNA derived from autologous cells. IFN-γ also induced the expression of TLR3, melanoma differentiation-associated gene 5, and retinoic acid-inducible gene I dsRNA receptors. Small interfering RNA knockdown revealed that TLR3 mediated VSMC activation by poly(I:C), whereas melanoma differentiation-associated gene 5 was more important for VSMC stimulation by self-RNA. IFN-γ–mediated induction of dsRNA receptors and priming for inflammatory responses to poly(I:C) was confirmed in vivo using immunodeficient mice bearing human coronary artery grafts. These findings suggest that IFN-γ, and by inference adaptive immunity, sensitizes the vasculature to innate immune activators, such as RNA, and activation of IFN-γ–primed vascular cells by exogenous or endogenous sources of RNA may contribute to the inflammatory milieu of arteriosclerosis.

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“…Experimentally, the response to dsRNA is measured using the synthetic analogue polyinosinic acid:cytidylic acid (poly(I:C)), which stimulates secretion of the chemokine CXCL10 (formerly IP-10) [18-20], in some cell types in an entirely TLR3-dependent fashion [21]. CXCL10 is important to recruit and activate neutrophils, lymphocytes and NK cells [22-24], which are crucial to limit viral replication.…”

Section: Introductionmentioning

confidence: 99%

Smoking decreases the response of human lung macrophages to double-stranded RNA by reducing TLR3 expression

et al. 2013

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BackgroundCigarette smoking is associated with increased frequency and duration of viral respiratory infections, but the underlying mechanisms are incompletely defined. We investigated whether smoking reduces expression by human lung macrophages (Mø) of receptors for viral nucleic acids and, if so, the effect on CXCL10 production.MethodsWe collected alveolar macrophages (AMø) by bronchoalveolar lavage of radiographically-normal lungs of subjects undergoing bronchoscopies for solitary nodules (n = 16) and of volunteers who were current or former smokers (n = 7) or never-smokers (n = 13). We measured expression of mRNA transcripts for viral nucleic acid receptors by real-time PCR in those AMø and in the human Mø cell line THP-1 following phorbol myristate acetate/vitamin D3 differentiation and exposure to cigarette smoke extract, and determined TLR3 protein expression using flow cytometry and immunohistochemistry. We also used flow cytometry to examine TLR3 expression in total lung Mø from subjects undergoing clinically-indicated lung resections (n = 25). Of these, seven had normal FEV1 and FEV1/FVC ratio (three former smokers, four current smokers); the remaining 18 subjects (14 former smokers; four current smokers) had COPD of GOLD stages I-IV. We measured AMø production of CXCL10 in response to stimulation with the dsRNA analogue poly(I:C) using Luminex assay.ResultsRelative to AMø of never-smokers, AMø of smokers demonstrated reduced protein expression of TLR3 and decreased mRNA for TLR3 but not TLR7, TLR8, TLR9, RIG-I, MDA-5 or PKR. Identical changes in TLR3 gene expression were induced in differentiated THP-1 cells exposed to cigarette smoke-extract in vitro for 4 hours. Among total lung Mø, the percentage of TLR3-positive cells correlated inversely with active smoking but not with COPD diagnosis, FEV1% predicted, sex, age or pack-years. Compared to AMø of never-smokers, poly(I:C)-stimulated production of CXCL10 was significantly reduced in AMø of smokers.ConclusionsActive smoking, independent of COPD stage or smoking duration, reduces both the percent of human lung Mø expressing TLR3, and dsRNA-induced CXCL10 production, without altering other endosomal or cytoplasmic receptors for microbial nucleic acids. This effect provides one possible mechanism for increased frequency and duration of viral lower respiratory tract infections in smokers.Trial registrationClinicalTrials.gov NCT00281190, NCT00281203 and NCT00281229.

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Opposing roles of RNA receptors TLR3 and RIG-I in the inflammatory response to double-stranded RNA in a Kaposi’s sarcoma cell line

Cited by 15 publications

References 31 publications

MDA5 complements TLR3 in suppression of neuroblastoma

MDA5 complements TLR3 in suppression of neuroblastoma

IFN-γ Primes Intact Human Coronary Arteries and Cultured Coronary Smooth Muscle Cells to Double-Stranded RNA- and Self-RNA–Induced Inflammatory Responses by Upregulating TLR3 and Melanoma Differentiation-Associated Gene 5

Smoking decreases the response of human lung macrophages to double-stranded RNA by reducing TLR3 expression

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