Transcriptional Induction of Multiple Cytokines by Human Respiratory Syncytial Virus Requires Activation of NF-κB and Is Inhibited by Sodium Salicylate and Aspirin

Bitko, Vira; Velazquez, Andrew; Yang, Liu; Yi, Yang; Barik, Sailen

doi:10.1006/viro.1997.8582

Cited by 140 publications

(138 citation statements)

References 51 publications

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“…To investigate the role of NF-nB in bone tumor burden and associated tumormediated osteolysis, a recombinant retrovirus containing a mInB expression cassette and a neomycin drug resistance marker were used to generate cells that stably express the mInB. The mInB cassette was mutated by replacing Ser 32 and Ser 36 with alanines. The mInB binds NF-nB, but because the mInB cannot be phosphorylated at two key sites NF-nB signal transduction is suppressed.…”

Section: Resultsmentioning

confidence: 99%

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

et al. 2005

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A central mediator of a wide host of target genes, the nuclear factor-KB (NF-KB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-KB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the boneseeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IKB that prevents phosphorylation of IKBa and associated nuclear translocation of NF-KB. Blockade of NF-KB signaling in MDA-MB-231 cells by the mutant IKB decreased in vitro cell proliferation, expression of the proinflammatory, bone-resorbing cytokine interleukin-6, and in vitro bone resorption by tumor/osteoclast cocultures while reciprocally up-regulating production of the proapoptotic enzyme caspase-3. Suppression of NF-KB transcription in these breast cancer cells also reduced incidence of in vivo tumor-mediated osteolysis after intratibial injection of tumor cells in female athymic nude mice. Immunohistochemistry showed that the cancerous lesions formed in bone by MDA-MB-231 cells express both interleukin-6 and the p65 subunit of NF-KB at the bone-tumor interface. NF-KB signaling in breast cancer cells therefore promotes bone tumor burden and tumor-mediated osteolysis through combined control of tumor proliferation, cell survival, and bone resorption. These findings imply that NF-KB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden. (Cancer Res 2005; 65(8): 3209-17)

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Section: Resultsmentioning

confidence: 99%

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

et al. 2005

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“…Engagement of TLR4 initiates an intracellular signaling cascade leading to activation of transcription factors responsible for initiation of transcription of proinflammatory genes. NF-B is central to expression of most of these genes (22,23). In resting cells, NF-B is sequestered in the cytoplasm by interaction with the IB (inhibitor of NF-B) family of inhibitory proteins.…”

Section: Reduced Ib␣ Phosphorylation In Pbmc From Patients Heterozygomentioning

confidence: 99%

TLR4 Polymorphisms Mediate Impaired Responses to Respiratory Syncytial Virus and Lipopolysaccharide

Tulic

Hurrelbrink²,

Prêle³

et al. 2007

The Journal of Immunology

125

108

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Severe bronchiolitis following respiratory syncytial virus (RSV) infection occurs in only a small subset of infected infants and the basis for variations in disease severity is not understood. Innate immune responses to RSV are mediated by TLR-4, and the 299Gly and 399Ile alleles of the TLR4 gene have been linked epidemiologically with increased severity of RSV disease in children. We hypothesized that cellular immune responses to RSV mediated by these variant forms of the receptor are defective relative to responses mediated via the common form of the receptor. Human bronchial epithelial cells were transfected with TLR4 constructs encoding the common TLR4 gene sequence (299Asp/399Thr), or the 299Gly or 399Ile alleles, and cytokine responses to in vitro RSV challenge were analyzed in the different transfected cells. Follow-up studies compared RSV-induced responses in PBMC from children expressing these same TLR4 genotypes. Human bronchial epithelial expressing 299Gly or 399Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-κB signaling post-TLR4 engagement, reduced production of IFNs, IL-8, IL-10, IL-12p35, IL-18, and CCL8, and the absence of acute-phase TNF-α. These findings were mirrored by blunted PBMC responses to RSV in children expressing the same TLR4 variants. Compromised first-line defense against RSV at the airway-epithelial surface of children expressing these TLR4 variants may thus confer increased susceptibility to severe infections with this virus.

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“…Furthermore, in mammalian and plant cells, this compound has been reported to impact intracellular signaling processes and the cytokine network (6,7). We recently showed that treatment of an invasive experimental S. aureus infection (endocarditis) with intravenous aspirin caused a significant reduction in bacterial densities within target tissues (vegetations and kidneys), and that these effects are mediated by salicylic acid (8).…”

Section: Introductionmentioning

confidence: 99%

Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus

Kupferwasser¹,

Yeaman²,

Nast³

et al. 2003

J. Clin. Invest.

137

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Aspirin has been previously shown to reduce the in vivo virulence of Staphylococcus aureus in experimental endocarditis, through antiplatelet and antimicrobial mechanisms. In the present study, salicylic acid, the major in vivo metabolite of aspirin, mitigated two important virulence phenotypes in both clinical and laboratory S. aureus strains: α-hemolysin secretion and fibronectin binding in vitro. In addition, salicylic acid reduced the expression of the α-hemolysin gene promoter, hla, and the fibronectin gene promoter, fnbA. Transcriptional analysis, fluorometry, and flow cytometry revealed evidence of salicylic acid-mediated activation of the stress-response gene sigB. Expression of the sigBrepressible global regulon sarA and the global regulon agr were also mitigated by salicylic acid, corresponding to the reduced expression of the hla and fnbA genes in vitro. Studies in experimental endocarditis confirmed the key roles of both sarA and sigB in mediating the antistaphylococcal effects of salicylic acid in vivo. Therefore, aspirin has the potential to be an adjuvant therapeutic agent against endovascular infections that result from S. aureus, by downmodulating key staphylococcal global regulons and structural genes in vivo, thus abrogating relevant virulence phenotypes.

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Transcriptional Induction of Multiple Cytokines by Human Respiratory Syncytial Virus Requires Activation of NF-κB and Is Inhibited by Sodium Salicylate and Aspirin

Cited by 140 publications

References 51 publications

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

TLR4 Polymorphisms Mediate Impaired Responses to Respiratory Syncytial Virus and Lipopolysaccharide

Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus

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