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Response to LPS of WT and IRAK4 kinase dead mouse bone marrow macrophages

ABSTRACT: IRAK-4 is an essential component of the signal transduction complex downstream of the IL-1- and Toll-like receptors. Though regarded as the first kinase in the signaling cascade, the role of IRAK-4 kinase activity versus its scaffold function is still controversial. In order to investigate the role of IRAK-4 kinase function in vivo, ‘knock-in’ mice were generated by replacing the wild type IRAK-4 gene with a mutant gene encoding kinase deficient IRAK-4 protein (IRAK-4 KD). Analysis of bone marrow macrophages obtained from WT and IRAK-4 KD mice with a number of experimental techniques demonstrated that the IRAK-4 KD cells greatly lack responsiveness to stimulation with the Toll-like receptor 4 (TLR4) agonist LPS. One of the techniques used, microarray analysis, identified IRAK-4 kinase-dependent LPS response genes and revealed that the induction of LPS-responsive mRNAs was largely ablated in IRAK-4 KD cells. In summary, our results suggest that IRAK-4 kinase activity plays a critical role in TLR4-mediated induction of inflammatory responses. Keywords: genetic modification, strain comparison, cell stimulation, time course, anti-bacterial response, innate immune response, inflammatory response

ORGANISM(S): Mus musculus

PROVIDER: GSE9037 | GEO | 2008/06/25

SECONDARY ACCESSION(S): PRJNA102541

REPOSITORIES: GEO

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Transcription profiling of mouse bone marrow macrophages from WT and IRAK4 kinase

Project description:IRAK-4 is an essential component of the signal transduction complex downstream of the IL-1- and Toll-like receptors. Though regarded as the first kinase in the signaling cascade, the role of IRAK-4 kinase activity versus its scaffold function is still controversial. In order to investigate the role of IRAK-4 kinase function in vivo, âknock-inâ mice were generated by replacing the wild type IRAK-4 gene with a mutant gene encoding kinase deficient IRAK-4 protein (IRAK-4 KD). Analysis of bone marrow macrophages obtained from WT and IRAK-4 KD mice with a number of experimental techniques demonstrated that the IRAK-4 KD cells greatly lack responsiveness to stimulation with the Toll-like receptor 4 (TLR4) agonist LPS. One of the techniques used, microarray analysis, identified IRAK-4 kinase-dependent LPS response genes and revealed that the induction of LPS-responsive mRNAs was largely ablated in IRAK-4 KD cells. In summary, our results suggest that IRAK-4 kinase activity plays a critical role in TLR4-mediated induction of inflammatory responses. Experiment Overall Design: The response of mouse bone marrow macrophages from WT and IRAK4 kinase dead animals to stimulation with LPS at two time points was determined. There were 12 samples in total, 6 from WT and 6 from IRAK4 kinase dead cells; for each strain there were 3 conditions: growth for 4 hours without stimulation (the strain-specific control), growth for 1 hour with stimulation, and growth for 4 hours with stimulation; for each condition there were two biological replicates.

2008-10-20 | E-GEOD-9037 | biostudies-arrayexpress

response to IL-1b of WT and IRAK4 kinase dead mouse embryonic fibroblasts

Project description:IRAK-4 is an essential component of the signal transduction complex downstream of the IL-1- and Toll-like receptors. Though regarded as the first kinase in the signaling cascade, the role of IRAK-4 kinase activity versus its scaffold function is still controversial. In order to investigate the role of IRAK-4 kinase function in vivo, ‘knock-in’ mice were generated by replacing the wild type IRAK-4 gene with a mutant gene encoding kinase deficient IRAK-4 protein (IRAK-4 KD). Analysis of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice with a number of experimental techniques demonstrated that they greatly lack responsiveness to stimulation with IL-1b or a Toll-like receptor 7 (TLR7) agonist. One of the techniques used, microarray analysis, identified IRAK-4 kinase-dependent IL-1b response genes in mouse embryonic fibroblasts and revealed that the induction of IL-1b-responsive mRNAs was largely ablated in IRAK-4 KD cells. In summary, our results suggest that IRAK-4 kinase activity plays a critical role in IL-1R/TLR7-mediated induction of inflammatory responses. Keywords: genetic modification, strain comparison, cell stimulation, time course, inflammatory response

2007-03-30 | GSE6789 | GEO

Transcription profiling of mouse embryonic fibroblasts from wild type and IRAK-4 kinase dead animals stimulated with IL-1b for different durations to identify IRAK-4 kinase-dependent IL-1b response genes.

Project description:IRAK-4 is an essential component of the signal transduction complex downstream of the IL-1- and Toll-like receptors. Though regarded as the first kinase in the signaling cascade, the role of IRAK-4 kinase activity versus its scaffold function is still controversial. In order to investigate the role of IRAK-4 kinase function in vivo, knock-in mice were generated by replacing the wild type IRAK-4 gene with a mutant gene encoding kinase deficient IRAK-4 protein (IRAK-4 KD). Analysis of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice with a number of experimental techniques demonstrated that they greatly lack responsiveness to stimulation with IL-1b or a Toll-like receptor 7 (TLR7) agonist. One of the techniques used, microarray analysis, identified IRAK-4 kinase-dependent IL-1b response genes in mouse embryonic fibroblasts and revealed that the induction of IL-1b-responsive mRNAs was largely ablated in IRAK-4 KD cells. In summary, our results suggest that IRAK-4 kinase activity plays a critical role in IL-1R/TLR7-mediated induction of inflammatory responses. Experiment Overall Design: The response of mouse embryonic fibroblasts from WT and IRAK4 kinase dead animals to stimulation with IL-1b at two time points was determined. There were 12 samples in total, 6 from WT and 6 from IRAK4 kinase dead cells; for each strain there were 3 conditions: growth for 4 hours without stimulation (the strain-specific control), growth for 1 hour with stimulation, and growth for 4 hours with stimulation; for each condition there were two biological replicates.

2007-11-15 | E-GEOD-6789 | biostudies-arrayexpress

RAW macrophages: Control vs. LPS treated or Immunobiotic treated

Project description:The ability of Lactiplantibacillus plantarum LOC1 and LOC3, originally isolated from fresh tea leaves, to modulate the response of murine macrophages to the activation of Toll-like receptor 4 (TLR4) by the stimulation with lipopolysaccharide (LPS) was evaluated.

2022-10-22 | GSE213389 | GEO

LPS-induced gene expression in mouse small intestinal epithelial cells

2010-08-29 | GSE23755 | GEO

LPS-induced gene expression in mouse small intestinal epithelial cells

Project description:Intestinal epithelial cells express the lipopolysaccharide (LPS) receptor Toll-like receptor (TLR4) and are responsive to LPS stimulation. Following LPS exposure, epithelial cells, similar to myeloid cells such as macrophages, acquire a state of tolerance. Innate immune tolerance is characterized by a lack of expression of proinflammatory genes in response to repeated stimulation. Tolerant epithelial cells, however, exhibit sustained expression of a distinct set of genes encoding for proteins involved in metabolism and homeostasis. This study comparatively analyzes the gene expression profile 6 hours after LPS stimulation (acute response) versus 6 hours LPS followed by 90 hours incubation in the absence of LPS (tolerant response). We used microarrays to detail the global program of gene expression under unstimulated (control), LPS stimulated (6 hours), and tolerant (96 hours) conditions. Three biological replicates each from naive cells, 6 hour LPS-stimulated cells, and 6 hour LPS-stimulated plus 90 hour LPS-free medium-incubated cells were examined and compared.

2010-08-29 | E-GEOD-23755 | biostudies-arrayexpress

Expression data from MALP-2-stimulated macrophages from wild-type, IRAK-2-/- and IRAK-1-/IRAK-2-/- mice

Project description:IL-1R-associated kinases (IRAKs) participate in Toll-like receptor (TLR) signal transduction. MALP-2 is a TLR2 ligand, and stimulation of macrophages with MALP-2 activates expression of various genes including proinflammatory cytokines. We used microarrays to examine influence of IRAK-2 or IRAK-1/IRAK-2 deficiency in MALP-2-inducible gene expression. Keywords: Time course after MALP-2 stimulation

2008-03-08 | GSE10765 | GEO

Transcription profiling of responses to TNF-alpha, IL-1beta, peptidoglycan or lipopolysaccharide (TLR2/4 agonists) evaluated at 4 hrs in peripheral blood monocytes (PBM) from the patient bearing the IRAK4 Q293X mutation vs PBM from 5 healthy individuals

Project description:IL-1R associated kinase-4 (IRAK4) is a key enzyme required for activation of the common Toll-like Receptor (TLR) signaling cascade, which results in the transcription of inflammatory and immunity genes. IRAK-4 deficiency has recently been described as a rare form of innate immunodeficiency. Patients present with pyogenic bacterial infections and bacteraemia, particularly with Gram+ Streptococcus pneumoniae, and isolated PBMC from these patients fail to produce inflammatory cytokines in response to TLR agonists. We embarked on this study for several purposes: (1) to identify defective gene response resulting from IRAK4-deficiency that are responsible for the patients' susceptibility to infection by particular bacteria (2) to identify genetic responses that confer relatively normal immunity in these patients despite having a defect in such a critical component of the innate immune system (3) to gain understanding of the transcriptional regulation of inflammatory genes (4) to gain insight into TLR signal transduction pathways, in particular, the role of IRAK4 in the TLR2 and TLR4 pathways initiated by Gram+ and Gram- bacterial components respectively. Transcriptional responses to TNF-alpha, IL-1beta, peptidoglycan or lipopolysaccharide (TLR2/4 agonists) were evaluated at 4 hrs in peripheral blood monocytes (PBM) from the patient bearing the IRAK4 Q293X mutation compared to PBM from 5 healthy individuals.

2010-05-19 | E-FPMI-7 | biostudies-arrayexpress

Effect of simultaneous activation of TGFbeta and TLR4 pathway in human monocytes

Project description:To better understand the interaction of TGFbeta and Toll-like-receptor 4 (TLR4) signaling in monocytes, we performed microarray analysis. We identified a unique set of genes whose expressions in monocytes were regulated by simultaneous stimulation of TLR4 and TGFβ signaling. THP-1 cells, a human monocytic cell line, were stimulated for 24 hours with PBS as control, LPS (100ng/ml), TGFbeta1 (1ng/ml) or LPS (100ng/ml) + TGFbeta1 (1ng/ml). After 24 hours of stimulation, total RNA was isolated and prepared for genome wide analyses using Illumina HumanRef8 V3.0 Beadchips. In total 32 arrays were analyzed including 8 samples of PBS-stimulated monocytes, 8 samples of LPS-stimulated monocytes, 8 samples of TGFbeta1 stimulated monocytes and 8 samples of monocytes stimulated with LPS + TGFbeta1.

2012-12-15 | E-GEOD-17909 | biostudies-arrayexpress

Disabled-2 is a negative immune regulator of lipopolysaccharide-stimulated Toll-like receptor 4 internalization and signaling

Project description:Toll-like receptor 4 (TLR4) plays a pivotal role in the host response to lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria. Here we elucidated whether the endocytic adaptor protein Disabled-2 (Dab2) that is abundantly expressed in the macrophages plays a role in LPS-stimulated TLR4 signaling and trafficking. Molecular analysis and transcriptome profiling of the RAW264.7 macrophage-like cells expressing short-hairpin RNA of Dab2 revealed that Dab2 mainly regulated LPS-stimulated TRIF-dependent, but not MyD88-dependent TLR4 signaling. Consequently, knockdown of Dab2 augmented TRIF-dependent interferon regulatory factor 3 activation and the expression for the subsets of inflammatory cytokines and interferon-inducible genes. We further delineated that Dab2 acted as a “clathrin sponge” and sequestered clathrin from TLR4/MD2 complex in the resting stage of macrophages. Clathrin was released from Dab2 and associated with TLR4 to facilitate the internalization of TLR4/MD2 complex together with the bound ligand from the cell surface upon LPS stimulation. Dab2 thereby functions as a negative immune regulator of TLR4 endocytosis and signaling, supporting a novel role of Dab2-associated regulatory circuit in the control of inflammatory response of macrophage to endotoxin.

2017-02-09 | GSE81088 | GEO

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