JNK2 and IKKβ Are Required for Activating the Innate Response to Viral Infection

Chu, Weihua; Ostertag, Derek; Li, Zhi Wei; Chang, Louise; Chen, Yi; Hu, Yinling; Williams, Bryan R.G.; Perrault, Jacques; Karin, Michael

doi:10.1016/s1074-7613(00)80146-6

Cited by 361 publications

(349 citation statements)

References 67 publications

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“…PKR is involved in the induction of IFN-a by dsRNA and many other viral infections, such as herpes simplex virus. [18][19][20] It has been reported that replication and transcription of the viral genome of single-stranded viral RNA viruses and many DNA viruses often lead to the formation of cytosolic dsRNA. 45,46 Thus, dsRNA could induce PKR activation.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] To discover whether PKR or DNA-PK was involved in IFN-a production, PBMCs stimulated with VZV were cocultured with and without 2AP (PKR inhibitor) or DMNB (DNA-PK inhibitor) for 48 h. We found that 2AP, but not DMNB, could block VZV-induced IFN-a production (Figure 3a). An MTT test was performed under the same conditions to exclude drug toxicity, and cell viability was not decreased by the addition of 2AP or DMNB (data not shown).…”

Section: Ifn-a Production In Vzv Infectionsmentioning

confidence: 95%

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IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

Huang

Kuo

et al. 2011

Cell Mol Immunol

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Understanding the defense mechanisms of the host of an organism is important for infection control. In previous studies, we demonstrated that interferon-a (IFN-a), but not IL-12, was produced by human peripheral blood mononuclear cells infected with varicella-zoster virus (VZV). Here, we investigated what kind of cell(s) and which signal molecule(s) are involved in IFN-a production. Using cell isolation and ELISA, we found that plasmacytoid dendritic cells (pDCs) were responsible for IFN-a production during VZV infection. We also found that Toll-like receptor 9 (TLR9) was involved in VZV-induced IFN-a production because inhibitory CpG oligodeoxynucleotide inhibited IFN-a production. UV-inactivated VZV-induced IFN-a production was lower than that of active VZV, indicating another TLR9-independent pathway. Further studies demonstrated that double-stranded RNA-dependent protein kinase, but not DNA-dependent protein kinase was involved in VZV-induced IFN-a production. Together, these results suggest that pDCs play an important role in IFN-a production during VZV infection through TLR9-dependent and -independent pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Ifn-a Production In Vzv Infectionsmentioning

confidence: 95%

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

Huang

Kuo

et al. 2011

Cell Mol Immunol

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“…Despite their structural similarity, IKK␣ and IKK␤ play distinct roles with respect to NF-B activation. Whereas IKK␤ is responsible for I B␣ phosphorylation and subsequent activation of "classical" NF-B complexes containing the p65 and p50 subunits in response to proinflammatory stimuli (3)(4)(5), the IKK␣ subunit is involved in an "alternative" signaling pathway that leads to the processing of the p100 subunit to p52 (1,6). This alternative pathway is not involved in innate immune responses or inflammation, but it instead plays a central role in adaptive immunity by influencing B cell development and lymphoid organogenesis.…”

mentioning

confidence: 99%

Amelioration of acute inflammation by systemic administration of a cell‐permeable peptide inhibitor of NF‐κB activation

Meglio

Ianaro

Ghosh

2005

Arthritis & Rheumatism

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Objective. We used an experimental model of inflammation in mice, carrageenan-induced paw edema, to study the antiinflammatory effects of the NEMObinding domain (NBD) peptide, which blocks activation of the inducible transcription factor NF-B.Methods. Paw edema was induced by subplantar injection of 1% -carrageenan into the mouse left hind paw. Test agents were given intraperitoneally immediately after carrageenan injection. The increase in footpad thickness was considered to be edema. In some experiments, the mice were killed and the paws were removed for histologic and molecular biology analysis. NF-B DNA binding activity was evaluated in nuclear extracts by electrophoretic mobility shift assays. The expression levels of NF-B-regulated cyclooxygenase 2 (COX-2) protein and tumor necrosis factor ␣ (TNF␣) messenger RNA (mRNA) were evaluated by immunoblot analysis and polymerase chain reaction amplification of reverse-transcribed mRNA, respectively.Results. We found that systemically administered NBD peptide significantly inhibited edema formation and cellular infiltration in inflamed mouse paws. This antiinflammatory activity was most likely due to inhibition of expression of proinflammatory mediators, such as TNF␣ and COX-2, in inflamed tissues. Conclusion.These studies further establish NF-B as a target for antiinflammatory therapy and provide support for the use of the NBD peptide as a possible therapeutic agent for inflammatory diseases.

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“…Following stimulation by proinflammatory cytokines, dsRNA, or viral infection, I B is phosphorylated, ubiquitinated, and targeted for degradation by the 26S proteasome (11,12). In vitro studies have shown that PKR has the ability to phosphorylate I B (13), and dsRNA-and virus-stimulated NF-B nuclear localization and DNA binding activities are attenuated in fibroblast cell lines deficient in PKR (13)(14)(15). The mechanism by which PKR stimulates NF-B activation is associated with the activation of I B kinase (IKK).…”

mentioning

confidence: 99%

Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

Steer¹,

Moran

Maggi³

et al. 2003

The Journal of Immunology

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In this study the regulation of macrophage expression of cyclooxygenase-2 (COX-2) in response to dsRNA and virus infection was examined. Treatment of RAW 264.7 macrophages with dsRNA results in COX-2 mRNA accumulation and protein expression and the production of PGE2. Similar to dsRNA, encephalomyocarditis virus (EMCV) infection of RAW 264.7 cells stimulates COX-2 expression and PGE2 accumulation. The dsRNA-dependent protein kinase (PKR), which has been shown to participate in the regulation of gene expression in response to dsRNA and virus infection, does not appear to participate in the regulation of COX-2 expression by macrophages. Expression of dominant negative mutants of PKR in RAW 264.7 cells fails to attenuate dsRNA- and EMCV-induced COX-2 expression or PGE2 production. Furthermore, dsRNA and EMCV stimulate COX-2 expression and PGE2 accumulation to similar levels in macrophages isolated from wild-type and PKR-deficient mice. Recently, a novel PKR-independent role for the calcium-independent phospholipase A2 (iPLA2) in the regulation of inducible NO synthase expression by macrophages in response to virus infection has been identified. The selective iPLA2 suicide substrate inhibitor bromoenol lactone prevents dsRNA- and EMCV-stimulated inducible NO synthase expression; however, bromoenol lactone does not attenuate dsRNA- or EMCV-induced COX-2 expression by macrophages. In contrast, inhibition of NF-κB activation prevents dsRNA-stimulated COX-2 expression and PGE2 accumulation by macrophages. These findings indicate that virus infection and treatment with dsRNA stimulate COX-2 expression by a mechanism that requires the activation of NF-κB and that is independent of PKR or iPLA2 activation.

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JNK2 and IKKβ Are Required for Activating the Innate Response to Viral Infection

Cited by 361 publications

References 67 publications

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

Amelioration of acute inflammation by systemic administration of a cell‐permeable peptide inhibitor of NF‐κB activation

Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

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