Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA154219 | ENA |
REPOSITORIES: ENA
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Project description:Our recent study of gene expression in mice treated with LPS systemically identified the E2F1 transcription factor as a novel regulator of innate immune response in lung, liver, and spleen tissue. Our follow up studies showed that RNAi-mediated inhibition or E2F1 gene deficiency lead to reduced inflammatory response to LPS in vitro and in vivo. Furthermore, a clear role for the role of miRNAs in the regulation of innate immune response to LPS has emerged. In the current study, we further examined B6;129E2F1-/- and B6x126 F2 mice in the systemic LPS model and used gene expression profiling to identify a defect in the coagulation cascade that contributes to increased morbidity of B6;129E2F1-/- mice despite their reduced systemic inflammatory response. We also studied miRNA expression profiles identified miRNAs that are differentially expressed in B6;129E2F1-/- but not B6x129 F2 mice. 32 mice (4-6) per group, E2F+/+ or E2F-/- genotype, treated with saline or LPS, 6 or 20 hrs
2012-06-30 | E-GEOD-33901 | biostudies-arrayexpress
Project description:Our recent study of gene expression in mice treated with LPS systemically identified the E2F1 transcription factor as a novel regulator of innate immune response in lung, liver, and spleen tissue. Our follow up studies showed that RNAi-mediated inhibition or E2F1 gene deficiency lead to reduced inflammatory response to LPS in vitro and in vivo. Furthermore, a clear role for the role of miRNAs in the regulation of innate immune response to LPS has emerged. In the current study, we further examined B6;129E2F1-/- and B6x126 F2 mice in the systemic LPS model and used gene expression profiling to identify a defect in the coagulation cascade that contributes to increased morbidity of B6;129E2F1-/- mice despite their reduced systemic inflammatory response. We also studied miRNA expression profiles identified miRNAs that are differentially expressed in B6;129E2F1-/- but not B6x129 F2 mice. 32 mice (4-6) per group, E2F+/+ or E2F-/- genotype, treated with saline or LPS, 6 or 20 hrs
2012-06-30 | E-GEOD-33900 | biostudies-arrayexpress
Project description:The Role of the E2F1 transcription factor in the innate immune response to systemic LPS [miRNA]
| PRJNA154217 | ENA
Project description:Our recent study of gene expression in mice treated with LPS systemically identified the E2F1 transcription factor as a novel regulator of innate immune response in lung, liver, and spleen tissue. Our follow up studies showed that RNAi-mediated inhibition or E2F1 gene deficiency lead to reduced inflammatory response to LPS in vitro and in vivo. Furthermore, a clear role for the role of miRNAs in the regulation of innate immune response to LPS has emerged. In the current study, we further examined B6;129E2F1-/- and B6x126 F2 mice in the systemic LPS model and used gene expression profiling to identify a defect in the coagulation cascade that contributes to increased morbidity of B6;129E2F1-/- mice despite their reduced systemic inflammatory response. We also studied miRNA expression profiles identified miRNAs that are differentially expressed in B6;129E2F1-/- but not B6x129 F2 mice.
2012-07-01 | GSE33901 | GEO
Project description:Our recent study of gene expression in mice treated with LPS systemically identified the E2F1 transcription factor as a novel regulator of innate immune response in lung, liver, and spleen tissue. Our follow up studies showed that RNAi-mediated inhibition or E2F1 gene deficiency lead to reduced inflammatory response to LPS in vitro and in vivo. Furthermore, a clear role for the role of miRNAs in the regulation of innate immune response to LPS has emerged. In the current study, we further examined B6;129E2F1-/- and B6x126 F2 mice in the systemic LPS model and used gene expression profiling to identify a defect in the coagulation cascade that contributes to increased morbidity of B6;129E2F1-/- mice despite their reduced systemic inflammatory response. We also studied miRNA expression profiles identified miRNAs that are differentially expressed in B6;129E2F1-/- but not B6x129 F2 mice.
2012-07-01 | GSE33900 | GEO
Project description:Background: Our understanding of the role host genetic factors play in the initiation and severity of infections caused by Gram negative bacteria is incomplete. Methods: To identify novel regulators of the host response to lipopolysaccharide (LPS), 11 inbred murine strains were challenged with LPS systemically. RNA from lung, liver, and spleen tissue was profiled on oligonucleotide microarrays to determine if unique transcripts differentiate susceptible and resistant strains of mice. Gene expression data were analyzed to identify over-represented pathways and transcription factors (TFs). The role of several TFs in innate immune response to LPS was examined by RNA interference in a mouse macrophage cell line. Mouse lines with targeted mutations were utilized to further confirm involvement of two novel genes in innate immunity. Results: In addition to two strains lacking functional TLR4 (C3H/HeJ and C57BL/6JTLR4-/-), three murine strains with functional TLR4 (C57BL/6, 129/SvlmJ, and NZW/LacJ) were found to be resistant to systemic LPS challenge; the other six strains were classified as sensitive. Gene expression analysis supports the involvement of a number of previously identified genes, molecular pathways, and TFs in the host response to LPS but also identifies Hedgehog signaling as a novel pathway activated by LPS. B6;129Ptch1+/+ wild-type mice were shown to be more sensitive to systemic LPS than B6;129Ptch1+/- heterozygote littermates further supporting the role of Hedgehog signaling in systemic LPS response. RNA interference-mediated inhibition of 6 TFs (C/EBP, Cdx-2, E2F1, Hoxa4, Nhlh1, and Tead2), out of 15 tested, was found to diminish production of IL-6 and TNF protein in murine macrophages. The role of E2F1 was confirmed by showing that B6;129E2F1-/- knockout mice are more sensitive to systemic LPS than wild-type controls. Conclusions: Our analysis of gene expression data identified novel pathways and transcription factors that regulate the host response to systemic LPS. Our results provide potential sepsis biomarkers and therapeutic targets that should be further investigated in human populations. Keywords: disease state analysis For each strain of mice, 6 mice were treated with LPS and 6 with saline. RNA of 3 animals was pooled to make two pools per condition (two biological replicates). Each pool was labeled with Cy3 and Cy5 and co-hybridized with Stratagene Univeral Mouse Reference (dye flip techical replicates). RNA from lung, liver, and spleen tissue was profiled on oligonucleotide microarrays
2009-07-01 | E-GEOD-14675 | biostudies-arrayexpress
Project description:Background: Our understanding of the role host genetic factors play in the initiation and severity of infections caused by Gram negative bacteria is incomplete. Methods: To identify novel regulators of the host response to lipopolysaccharide (LPS), 11 inbred murine strains were challenged with LPS systemically. RNA from lung, liver, and spleen tissue was profiled on oligonucleotide microarrays to determine if unique transcripts differentiate susceptible and resistant strains of mice. Gene expression data were analyzed to identify over-represented pathways and transcription factors (TFs). The role of several TFs in innate immune response to LPS was examined by RNA interference in a mouse macrophage cell line. Mouse lines with targeted mutations were utilized to further confirm involvement of two novel genes in innate immunity. Results: In addition to two strains lacking functional TLR4 (C3H/HeJ and C57BL/6JTLR4-/-), three murine strains with functional TLR4 (C57BL/6, 129/SvlmJ, and NZW/LacJ) were found to be resistant to systemic LPS challenge; the other six strains were classified as sensitive. Gene expression analysis supports the involvement of a number of previously identified genes, molecular pathways, and TFs in the host response to LPS but also identifies Hedgehog signaling as a novel pathway activated by LPS. B6;129Ptch1+/+ wild-type mice were shown to be more sensitive to systemic LPS than B6;129Ptch1+/- heterozygote littermates further supporting the role of Hedgehog signaling in systemic LPS response. RNA interference-mediated inhibition of 6 TFs (C/EBP, Cdx-2, E2F1, Hoxa4, Nhlh1, and Tead2), out of 15 tested, was found to diminish production of IL-6 and TNFalpha protein in murine macrophages. The role of E2F1 was confirmed by showing that B6;129E2F1-/- knockout mice are more sensitive to systemic LPS than wild-type controls. Conclusions: Our analysis of gene expression data identified novel pathways and transcription factors that regulate the host response to systemic LPS. Our results provide potential sepsis biomarkers and therapeutic targets that should be further investigated in human populations. Keywords: disease state analysis
2009-07-01 | GSE14675 | GEO
Project description:Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using p38γ/p38δ deficient (p38γ/δ-/-) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here we generated a p38γD171A/D171A/p38δ-/- (p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38γ/p38δ functions. p38γ/δKIKO mice showed a reduced inflammatory response and less susceptibility to LPS-induced septic shock and Candida albicans infection than wild-type mice. Gene expression analyses in LPS-activated WT and p38γ/δKIKO macrophages revealed that p38γ/p38δ regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and in vitro kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38γ/p38δ. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of iNOS and IL-1β mRNA. These results suggest that p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.
2023-08-10 | PXD042626 | Pride
Project description:Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important in innate immunity. Here, we show that T cell death-associated gene 51 (TDAG51/PHLDA1) is a novel coactivator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3 to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a coactivator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response.
2023-06-24 | PXD039815 | Pride