Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA106801 | ENA |
REPOSITORIES: ENA
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Project description:Synthetic oligonucleotides (ODNs) containing CpG motifs stimulate human plasmacytoid dendritic cells (pDCs) to produce type-1 interferons (IFN) and pro-inflammatory cytokines. Previous studies demonstrated that interferon regulatory factors (IRFs) played a central role in mediating CpG-induced pDC activation. This work explores the inverse effects of IRF-5 and IRF-8 on CpG dependent gene expression. Results from RNA interference and microarray studies indicate that IRF-5 up-regulates TLR9-driven gene expression whereas IRF-8 down-regulates the same genes. Several findings support the conclusion that IRF-8 inhibits TLR9 dependent gene expression by directly blocking the activity of IRF-5. First, the inhibitory activity of IRF-8 is only observed when IRF-5 is present. Second, proximity ligation analysis shows that IRF-8 and IRF-5 co-localize within the cytoplasm of resting human pDC and co-translocate to the nucleus after CpG stimulation. Taken together, these findings suggest that two transcription factors with opposing functions control TLR9 signaling in human pDCs.
2016-06-01 | GSE70429 | GEO
Project description:Suppression of TLR9-dependent gene expression in vivo mediated by TTAGGG motifs
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Project description:Synthetic oligonucleotides (ODNs) containing CpG motifs stimulate human plasmacytoid dendritic cells (pDCs) to produce type-1 interferons (IFN) and pro-inflammatory cytokines. Previous studies demonstrated that interferon regulatory factors (IRFs) played a central role in mediating CpG-induced pDC activation. This work explores the inverse effects of IRF-5 and IRF-8 on CpG dependent gene expression. Results from RNA interference and microarray studies indicate that IRF-5 up-regulates TLR9-driven gene expression whereas IRF-8 down-regulates the same genes. Several findings support the conclusion that IRF-8 inhibits TLR9 dependent gene expression by directly blocking the activity of IRF-5. First, the inhibitory activity of IRF-8 is only observed when IRF-5 is present. Second, proximity ligation analysis shows that IRF-8 and IRF-5 co-localize within the cytoplasm of resting human pDC and co-translocate to the nucleus after CpG stimulation. Taken together, these findings suggest that two transcription factors with opposing functions control TLR9 signaling in human pDCs. CAL-1 cells were transfected with siRNA targeting IRF-5 (IRF-5si) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats). CAL-1 cells were transfected with siRNA targeting IRF-8 (IRF-8si) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats). CAL-1 cells were transfected with control siRNA (Contsi) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats).
2016-06-01 | E-GEOD-70429 | biostudies-arrayexpress
Project description:Endosomal Toll-like receptors (TLRs) play an important role in the etiology of systemic autoimmune diseases such as SLE, where DNA- and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways, respectively. Nevertheless, TLR9-deficient autoimmune prone mice develop more severe clinical disease, while TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we have now directly compared the functional properties of autoantigen activated WT, TLR9-deficient and TLR7-deficient B cells, in an experimental system where proliferation depends on BCR/TLR co-engagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than either WT or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, and TLR7 to promote, the clinical features of SLE. AM14 WT, Tlr7-/-, Tlr9-/- and Tlr7/9-/- B cells were stimulated with PL2-3 for 0, 6, 24, and 42 hours, for a total of 16 samples.
2015-03-04 | E-GEOD-58756 | biostudies-arrayexpress
Project description:CpG DNA binds to Toll-like receptor 9 to stimulate a strong innate immune response. Despite extensive studies of TLR9 mediated signal transduction, the scope of CpG-induced changes in gene expression is incompletely understood. In particular, the prolonged effects of CpG ODN (oligodeoxynucleotide) on gene activation have not been investigated despite evidence that a single dose of CpG ODN alters immune reactivity for several weeks. This study used gene expression analysis to monitor changes in mRNA levels for 14 days, and identified the genes, pathways, functional groups and regulatory networks triggered in vivo following CpG ODN administration. Two discrete peaks of gene activation (at 3 hr and 5 days) were observed after CpG administration. Both the regulation and function of genes activated during the second peak differed from those triggered shortly after CpG administration. Initial gene up-regulation corresponded to a period when TLR9 ligation stimulated genes functionally associated with the generation of innate and adaptive immune responses (e.g. the NF-kB and B-cell receptor pathways). The second peak reflected processes associated with cell division (e.g., cell cycle and DNA replication & repair). Whereas TNF and IFNG played central roles regulating the first peak of activation, E2F1, E2F2, BRCA1, and HRAS had major impact on the networks controlling the second peak. The complex bimodal pattern of gene expression elicited by CpG ODN administration provides novel insights into the long term effects of CpG DNA on genes associated with immunity and cell proliferation. Data from 4 independent biological replicates/time point (9 time points) and 6 untreated controls were used for all statistical analyses. A reference design was used. Reference cDNA vs. sample cDNA were hybridized to same array.
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Project description:Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during lens and forebrain development
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Project description:Endosomal Toll-like receptors (TLRs) play an important role in the etiology of systemic autoimmune diseases such as SLE, where DNA- and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways, respectively. Nevertheless, TLR9-deficient autoimmune prone mice develop more severe clinical disease, while TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we have now directly compared the functional properties of autoantigen activated WT, TLR9-deficient and TLR7-deficient B cells, in an experimental system where proliferation depends on BCR/TLR co-engagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than either WT or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, and TLR7 to promote, the clinical features of SLE.
2015-03-04 | GSE58756 | GEO
Project description:CpG DNA interacts with TLR9 to stimulate a broadly protective innate immune response. This study uses bioinformatic network analysis of microarray data to identify the genes and regulatory networks triggered by CpG ODN. CpG treatment induced significant gene up-regulation (p < 0.00001) in the spleen within 30 min, peaking with the activation of >500 genes at 3 hr, and declining progressively thereafter. There were reproducible changes in the pattern of gene expression over time. This was mediated by a small group of “major inducers” (IL1A, IL1B, TNF, IFNG) whose activity was modulated by several “minor inducers” (NFKB1, IL6, IL15, IL18, STAT1, STAT2). The subsequent decline in gene activation was mediated by “suppressors” (MYC, IL1RN, SOCS1, SOCS3, NFKBIA, IL10, FOS) that actively down-regulated gene expression and targeted both major and minor inducers. Thus, the regulation of TLR9 dependent gene activation involves multiple waves of stimulation mediated by a small number of “major” and “minor” inducers followed by the active inhibition of gene expression by “suppressors”. Keywords: time series design
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Project description:Identification of Pax6-dependent gene regulatory networks in the mouse lens
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