Inhibition of γ-Secretase Cleavage in the Notch Signaling Pathway Blocks HSV-2-Induced Type I and Type II Interferon Production

Svensson, Alexandra; Jäkärä, Emely; Shestakov, Andrey; Eriksson, Kristina

doi:10.1089/vim.2010.0013

Cited by 8 publications

(7 citation statements)

References 30 publications

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“…However, a potent TLR stimulation using R848 induced the transcription of the three genes tested. DAPT treatment also blocked this induction, thus showing an interplay of Notch and TLR pathways in pDCs as well, as observed on HSV-2-stimulated human pDCs (57).…”

Section: Discussionsupporting

confidence: 61%

“…Foldi et al (42) demonstrated that TLR induction of Jag-1 in human macrophages was directed, dependent on Notch and RBP-J, and superinduced by IFN-g, whereas TLR-induced Dll expression was indirect (required de novo protein synthesis), independent of Notch and RBP-J and suppressed by IFN-g. Other stimuli, such as PGE 2 , cholera toxin, and TNF, seem to promote Jag2 expression (35, 55, 56). The different behavior of Notch Regarding pDCs, to date, only a single study reported the expression of Notch receptors and ligands in mouse splenic pDCs (33), and one recent study showed the expression of Notch-1 in human pDCs (57). Mouse splenic pDCs were found to express Dll1 and Dll4 but not Jag1 and Jag2, both highly expressed by human pDCs in our results.…”

Section: Discussioncontrasting

confidence: 50%

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Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

Pérez-Cabezas

Naranjo-Gómez

Bastos-Amador

et al. 2011

The Journal of Immunology

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Notch signaling is involved in multiple cellular processes. Recent data also support the prominent role of Notch signaling in the regulation of the immune response. In this study, we analyzed the expression and function of Notch receptors and ligands on both human blood conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs). The expression and modulation upon TLR activation of Notch molecules partially differed between cDCs and pDCs, but functional involvement of the Notch pathway in both cell types was clearly revealed by specific inhibition using DAPT. Beyond the induction of Notch target genes and modulation of maturation markers, Notch pathway was also involved in a differential secretion of some specific cytokines/chemokines by DC subsets. Whereas Notch ligation induced IL-10 and CCL19 secretion in cDCs, Notch inhibition resulted in a diminished production of these proteins. With regard to pDCs, Notch activation induced TNF-α whereas Notch inhibition significantly abrogated the secretion of CCL19, CXCL9, CXCL10, and TNF-α. Additionally, Notch modulation of DC subsets differentially affected Th polarization of allostimulated T cells. Our results suggest that the Notch pathway may function as an additional mechanism controlling human DC responses, with differential activity on cDCs and pDCs. This control mechanism may ultimately contribute to define the local milieu promoted by these cells under the particular conditions of the immune response.

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Section: Discussionsupporting

confidence: 61%

Section: Discussioncontrasting

confidence: 50%

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

Pérez-Cabezas

Naranjo-Gómez

Bastos-Amador

et al. 2011

The Journal of Immunology

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“…Jagged 2 is also upregulated by the alphaherpesviruses, HSV-1 and Psuedorabies viruses [59]. KSHV and EBV also exploit the notch signaling pathway to facilitate aspects of their life cycle [60] and notch signaling is proposed to influence HSV-2-induced interferon responses [61]. We show for the first time that the betaherpesvirus, MCMV, also influences notch signaling.…”

Section: Discussionmentioning

confidence: 77%

Dual Analysis of the Murine Cytomegalovirus and Host Cell Transcriptomes Reveal New Aspects of the Virus-Host Cell Interface

et al. 2013

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Major gaps in our knowledge of pathogen genes and how these gene products interact with host gene products to cause disease represent a major obstacle to progress in vaccine and antiviral drug development for the herpesviruses. To begin to bridge these gaps, we conducted a dual analysis of Murine Cytomegalovirus (MCMV) and host cell transcriptomes during lytic infection. We analyzed the MCMV transcriptome during lytic infection using both classical cDNA cloning and sequencing of viral transcripts and next generation sequencing of transcripts (RNA-Seq). We also investigated the host transcriptome using RNA-Seq combined with differential gene expression analysis, biological pathway analysis, and gene ontology analysis.We identify numerous novel spliced and unspliced transcripts of MCMV. Unexpectedly, the most abundantly transcribed viral genes are of unknown function. We found that the most abundant viral transcript, recently identified as a noncoding RNA regulating cellular microRNAs, also codes for a novel protein. To our knowledge, this is the first viral transcript that functions both as a noncoding RNA and an mRNA. We also report that lytic infection elicits a profound cellular response in fibroblasts. Highly upregulated and induced host genes included those involved in inflammation and immunity, but also many unexpected transcription factors and host genes related to development and differentiation. Many top downregulated and repressed genes are associated with functions whose roles in infection are obscure, including host long intergenic noncoding RNAs, antisense RNAs or small nucleolar RNAs. Correspondingly, many differentially expressed genes cluster in biological pathways that may shed new light on cytomegalovirus pathogenesis. Together, these findings provide new insights into the molecular warfare at the virus-host interface and suggest new areas of research to advance the understanding and treatment of cytomegalovirus-associated diseases.

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“…The use of non‐replicating virus instead of replication‐competent virus may of course explain why some of the virus tested did not induce any IFN‐α/β responses. Yet, HSV‐1 did not induce any IFN‐α in cord pDC despite the ability of replication‐deficient HSV in inducing strong type I interferon responses in adult cells [48, 49]. However, cord pDC have an impaired IFN‐α/β signalling capacity [23], which is as a result of a defect in interferon regulatory factor (IRF)‐7‐mediated responses in pDC from newborns [50].…”

Section: Discussionmentioning

confidence: 99%

Enveloped Virus but not Bacteria Block IL‐13 Responses in Human Cord Blood T Cells In Vitro

et al. 2012

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Infections that occur early in life may have a beneficial effect on the immune system and thereby reduce the risk of allergen sensitization and/or allergic disease. It is not yet clear to what extent specific virus and/or bacteria can mediate this effect. The purpose of this study was to assess the role of virus and bacteria in CD4+ T cell‐derived cytokine production in newborns. We compared the effects of five bacteria (Staphlococcus aureus, Escherichia coli, Clostridium difficile, Lactobacillus rhamnosus and Bifidobacterium bifidus) and seven virus (adenovirus, coronavirus, cytomegalovirus, herpes simplex virus, influenza virus, morbillivirus and poliovirus) on the Th1/Th2 cytokine production in mixed lymphocyte reactions using CD4+ T cells from cord blood cocultured with allogenic myeloid or plasmacytoid dendritic cells. When comparing the baseline cytokine production prior to microbial stimulation, we observed that cord plasmacytoid DC were stronger inducers of Th2 cytokines (IL‐5 and IL‐13) compared with cord myeloid DC and to adult DC. When adding microbes to these cultures, bacteria and virus differed in two major respects; Firstly, all enveloped viruses, but none of the bacteria, blocked Th2 (IL‐13) production by cord CD4+ cells. Secondly, all Gram‐positive bacteria, but none of the virus, induced IL‐12p40 responses, but the IL‐12p40 responses did not affect Th1 cytokine production (IFN‐γ). Instead, Th1 responses were correlated with the capacity to induce IFN‐α secretion, which in cord cells were induced by S. aureus and influenza virus alone. These data imply that enveloped virus can deviate Th2 responses in human cord T cells.

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Inhibition of γ-Secretase Cleavage in the Notch Signaling Pathway Blocks HSV-2-Induced Type I and Type II Interferon Production

Cited by 8 publications

References 30 publications

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

Dual Analysis of the Murine Cytomegalovirus and Host Cell Transcriptomes Reveal New Aspects of the Virus-Host Cell Interface

Enveloped Virus but not Bacteria Block IL‐13 Responses in Human Cord Blood T Cells In Vitro

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