TPL-2 inhibits interferon-beta expression via an ERK1/2-TCF-FOS axis in TLR4-stimulated macrophages
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ABSTRACT:
PROVIDER: PRJNA741502 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14916041.fastq.gz | Fastqsanger.gz | |||
| SRR14916042.fastq.gz | Fastqsanger.gz | |||
| SRR14916043.fastq.gz | Fastqsanger.gz | |||
| SRR14916044.fastq.gz | Fastqsanger.gz | |||
| SRR14916045.fastq.gz | Fastqsanger.gz |
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Project description:Studies in mice have indicated that TPL2 kinase plays important roles in immune responses to pathogens and in various models of inflammatory disease. We set out to determine how TPL2 (Map3k8) regulates transcription using an in vitro system of LPS-stimulated primary macrophages. TPL2 regulated genes are involved in a number of different processes including inflammation as well as reproduction, cell cycle and signal transduction. Differentially expressed genes were used in a K means analysis, grouping based on expression profile, which identified 12 different expression profiles. There was a strong correlation between rapidly-induced genes regulated by TPL2 kinase activity and their expression in cells treated with the MKK1/2 inhibitor (PD032590)1 or from cells where phosphorylation of P105 by IKK2 is blocked. Cluster 1 genes were found to be enriched for TCF family members. TPL2 was shown to regulate ELK1 phosphorylation and known TCF targets genes such as Egr1. TPL2 is known to regulate transcription of multiple cytokines and chemokines including IFNb. Like Map3k8[D270A] macrophages, expression of Ifnb1 was increased in Elk1-/-Elk4-/- macrophages compared to WT macrophages following LPS stimulation. In fact, this increase was also seen in MKK1/2 inhibitor treated macrophages. Expression of Fos was decreased in both Map3k8[D270A] and Elk1-/-Elk4-/- macrophages. Macrophages generated from mice with myeloid-specific deletion of Fos also had elevated levels of Ifnb1 compared to controls. Similar results were obtained following activation of TLR1/2, TLR9 and TNF-R in macrophages. Furthermore, LPS or TNF stimulation of MEFs lacking Elk1, Elk3 and Elk4 had reduced FOS protein levels and increased Ifnb1 mRNA suggesting a general role for ERK1/2 > TCF pathway regulating Ifnb1 levels through Fos expression.
2021-10-26 | GSE178921 | GEO
Project description:The TPL-2 – ERK1/2 signalling pathway inhibits interferon beta expression in macrophages via TCF-dependent Fos transcription
| PRJNA477798 | ENA
Project description:Studies in mice have indicated that TPL2 kinase plays important roles in immune responses to pathogens and in various models of inflammatory disease. We set out to determine how TPL2 (Map3k8) regulates transcription using an in vitro system of LPS-stimulated primary macrophages. TPL2 regulated genes are involved in a number of different processes including inflammation as well as reproduction, cell cycle and signal transduction. Differentially expressed genes were used in a K means analysis, grouping based on expression profile, which identified 12 different expression profiles. There was a strong correlation between rapidly-induced genes regulated by TPL2 kinase activity and their expression in cells treated with the MKK1/2 inhibitor (PD032590)1 or from cells where phosphorylation of P105 by IKK2 is blocked. Cluster 1 genes were found to be enriched for TCF family members. TPL2 was shown to regulate ELK1 phosphorylation and known TCF targets genes such as Egr1. TPL2 is known to regulate transcription of multiple cytokines and chemokines including IFNb. Like Map3k8[D270A] macrophages, expression of Ifnb1 was increased in Elk1-/-Elk4-/- macrophages compared to WT macrophages following LPS stimulation. In fact, this increase was also seen in MKK1/2 inhibitor treated macrophages. Expression of Fos was decreased in both Map3k8[D270A] and Elk1-/-Elk4-/- macrophages. Macrophages generated from mice with myeloid-specific deletion of Fos also had elevated levels of Ifnb1 compared to controls. Similar results were obtained following activation of TLR1/2, TLR9 and TNF-R in macrophages. Furthermore, LPS or TNF stimulation of MEFs lacking Elk1, Elk3 and Elk4 had reduced FOS protein levels and increased Ifnb1 mRNA suggesting a general role for ERK1/2 > TCF pathway regulating Ifnb1 levels through Fos expression.
2020-06-22 | GSE116220 | GEO
Project description:TPL-2 kinase plays an important role in innate immunity, activating ERK1/2 MAPKs in myeloid cells following TLR stimulation. We investigated how TPL-2 controls transcription in TLR4-stimulated mouse macrophages. TPL-2 activation of ERK1/2 regulated expression of genes encoding transcription factors, cytokines, chemokines, and signaling regulators. Bioinformatics analysis of gene clusters most rapidly induced by TPL-2 suggested that their transcription was mediated by the ternary complex factor (TCF) and FOS transcription factor families. Consistently, TPL-2 induced ERK1/2 phosphorylation of the ELK1 TCF and the expression of TCF target genes. Furthermore, transcriptomic analysis of TCF-deficient macrophages demonstrated that TCFs mediate approximately half of the transcriptional output of TPL-2 signaling, partially via induced expression of secondary transcription factors. TPL-2 signaling and TCFs were required for maximal TLR4-induced FOS expression. Comparative analysis of the transcriptome of TLR4-stimulated Fos -/- macrophages indicated that TPL-2 regulated a significant fraction of genes by controlling FOS expression levels. A key function of this ERK1/2-TCF-FOS pathway was to mediate TPL-2 suppression of type I IFN signaling, which is essential for host resistance against intracellular bacterial infection.
| S-EPMC9012084 | biostudies-literature
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 1] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL?12, IL?1 and TNF??, as well as IFN?? and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL?10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease. Macrophages were derived from C57Bl/6 bone marrow, plated and infected with Mtb H37Rv (or not) in duplicate wells. Samples were then harvested for RNA at time 0 (uninfected only), 15m, 30m, 1hr, 3hr, 6hr and 24hr.
2013-09-05 | E-GEOD-47672 | biostudies-arrayexpress
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 2] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL‐12, IL‐1 and TNF‐α, as well as IFN‐γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL‐10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease. Macrophages were derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNARKO bone marrow, plated and infected with Mtb H37Rv (or not) in triplicate wells. The indicated samples were also treated with 5ng/ml IFNgamma at the time of infection. Samples were then harvested for RNA at time 0, 1hr and 6hr. Please note that *Sample and *Medium control samples (e.g. '0hr TPL2-/-IFNabR-/- Sample' vs '0hr TPL2-/-IFNabR-/- Medium Control Sample') are the same sample group (i.e. uninfected) with one group being a repeat re-run of the other (indicated in the correponding SAMPLE description field).
2013-09-05 | E-GEOD-47673 | biostudies-arrayexpress
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 2] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL‐12, IL‐1 and TNF‐α, as well as IFN‐γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL‐10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease.
2013-09-05 | GSE47673 | GEO
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 1] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL‐12, IL‐1 and TNF‐α, as well as IFN‐γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL‐10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease.
2013-09-05 | GSE47672 | GEO
Project description:BACKGROUND & AIMS: TLR4 is an innate immune receptor with expression in human skin, keratinocytes as well as squamous cell carcinoma (SCC) of the skin. In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of primary normal, SCC-derived and HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1, and TFPI. In summary, TLR4 negatively regulates the proliferation of primary keratinocytes and its overexpression reduces tumor growth of SCC cells.
2016-11-16 | GSE89856 | GEO
Project description:Pairwise comparison of expression of alternate splicing in the Tlr4 pathway using custom designed Combimatix oligonucleotide arrays. Bone marrow derived macrophages (BMMs) from C57Bl6/J mice (6 wks male) exposed to LPS (10ng/ml) for 7hrs. Keywords: Response to LPS
2007-01-15 | GSE4044 | GEO