Mus musculus
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ABSTRACT:
PROVIDER: PRJNA99223 | ENA |
REPOSITORIES: ENA
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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
Project description:Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but so far success remains limited in the clinic. Furthermore, preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAFs) carries a risk of accelerating PDAC progression. These concerns underscore the need to concurrently target the key signaling mechanisms that drive the malignant attributes of both CAFs and PDAC cells. We previously reported that inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) suppresses NF-kB activity and promotes chemotherapy response in PDAC cells. In this study, we show that CAFs in PDAC tumors robustly express activated IRAK4 and NF-kb. The role of IRAK4 and NF-kB in PDAC CAFs has not been reported, and should be clarified before advancing IRAK4 inhibitors to the clinic. Using shRNAs and small molecular inhibitors, we found that IRAK4 is a key driver of NF-kB activity in CAFs. We showed that CAFs utilizes IRAK4 to drive tumor fibrosis, support PDAC cells proliferation, survival and chemoresistance in vitro and in vivo. From cytokine array analysis of CAFs and microarray analysis of PDAC cells, we identified IL-1b as a key cytokine that activates IRAK4 in CAFs. Targeting IRAK4 or IL-1b renders PDAC tumors less fibrotic and more sensitive to gemcitabine in vivo. Moreover, high IL-1b expression by immunohistochemistry in PDAC stroma is strongly associated with poor overall survival. Together, our studies established a tumor-stroma IL-1b-IRAK4 feedforward circuitry that can be therapeutically disrupted to render chemotherapy more effective in PDAC.
2018-01-26 | GSE73046 | GEO
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
Project description:response to LPS of WT and IRAK4 kinase dead mouse bone marrow macrophages
| PRJNA102541 | ENA
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
Project description:IRAK4 kinase plays a critical role in innate immune responses and inflammation by modulating the TLR/IL-1R signaling pathway, yet the mechanism by which it regulates downstream pathways and transcription factors to induce inflammatory cytokines is unclear. IRAK4 can mediate signaling events by mechanisms both dependent and independent of its kinase activity. Understanding this regulation is important for deciphering the role of IRAK4 and for the development of treatments for inflammatory diseases and cancer. Through transcriptomic and biochemical analyses of primary human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the transcription factor IRF5 which in turn induces inflammatory cytokine and type I interferon transcription in myeloid cells. We also show that IRAK4 kinase activity does not control activation of NF-κB. Following TLR stimulation, translocation of IRF5, but not NF-κB, to the nucleus in human monocytes is abolished by IRAK4 kinase inhibition. In addition, binding of IRF5, but not NF-κB p65, to promoters of inflammatory target genes (TNF-α and IP10) is blocked with an IRAK4 kinase inhibitor. IKKβ, a known activator of IRF5, is phosphorylated in response to TLR mediated signaling, and inhibition of IRAK4 kinase blocks IKKβ phosphorylation. Pharmacological inhibition of IKKβ and TAK1, the upstream kinase of IKKβ, in human monocytes blocks IL-1, IL-6 and TNF-α cytokine production, as well as IRF5 translocation to the nucleus. Taken together, our data suggest a novel mechanism by which IRAK4 kinase activity regulates TAK1 and IKKβ activation, leading to the translocation of IRF5 and induction of inflammatory cytokines in human monocytes.
2017-10-12 | GSE86234 | GEO
Project description:Chemical reprogramming of somatic cells into pluripotent or lineage-specific cells offers transformative potential for regenerative medicine but is limited by molecular barriers. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), a key innate immune kinase, as a previously unrecognized barrier to multi-lineage reprogramming. We discovered that pharmacological inhibition of IRAK4 potently enhances reprogramming of mouse embryonic fibroblasts (MEFs) through the chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, significantly increasing colony formation and expression of core XEN regulators (Sox17/Gata4/Sall4/Foxa2). Genetic knockdown of Irak4 similarly accelerated reprogramming, while its overexpression blocked cell fate transitions. Mechanistically, IRAK4 inhibition remodels cell cycle dynamics, shortening G0/G1 and lengthening G2/M phases to license transcriptional plasticity. Crucially, IRAK4 suppression also enhanced direct lineage conversion, boosting the efficiency and functional maturity of MEF-derived hepatocyte-like cells (iHeps) via elevated albumin/Cyp3a11 expression, glycogen storage, and detoxification capacity. These results establish IRAK4 as a druggable regulator that constrains cellular plasticity by coupling innate immune signaling to cell cycle control. Targeting IRAK4 refines reprogramming strategies to overcome somatic barriers, enhancing the generation of pluripotent and functional lineage-specific cells for regenerative applications.
2026-09-02 | GSE303074 | GEO
Project description:Chemical reprogramming of somatic cells into pluripotent or lineage-specific cells offers transformative potential for regenerative medicine but is limited by molecular barriers. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), a key innate immune kinase, as a previously unrecognized barrier to multi-lineage reprogramming. We discovered that pharmacological inhibition of IRAK4 potently enhances reprogramming of mouse embryonic fibroblasts (MEFs) through the chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, significantly increasing colony formation and expression of core XEN regulators (Sox17/Gata4/Sall4/Foxa2). Genetic knockdown of Irak4 similarly accelerated reprogramming, while its overexpression blocked cell fate transitions. Mechanistically, IRAK4 inhibition remodels cell cycle dynamics, shortening G0/G1 and lengthening G2/M phases to license transcriptional plasticity. Crucially, IRAK4 suppression also enhanced direct lineage conversion, boosting the efficiency and functional maturity of MEF-derived hepatocyte-like cells (iHeps) via elevated albumin/Cyp3a11 expression, glycogen storage, and detoxification capacity. These results establish IRAK4 as a druggable regulator that constrains cellular plasticity by coupling innate immune signaling to cell cycle control. Targeting IRAK4 refines reprogramming strategies to overcome somatic barriers, enhancing the generation of pluripotent and functional lineage-specific cells for regenerative applications.
2026-09-02 | GSE303073 | GEO
Project description:Chemical reprogramming of somatic cells into pluripotent or lineage-specific cells offers transformative potential for regenerative medicine but is limited by molecular barriers. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), a key innate immune kinase, as a previously unrecognized barrier to multi-lineage reprogramming. We discovered that pharmacological inhibition of IRAK4 potently enhances reprogramming of mouse embryonic fibroblasts (MEFs) through the chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, significantly increasing colony formation and expression of core XEN regulators (Sox17/Gata4/Sall4/Foxa2). Genetic knockdown of Irak4 similarly accelerated reprogramming, while its overexpression blocked cell fate transitions. Mechanistically, IRAK4 inhibition remodels cell cycle dynamics, shortening G0/G1 and lengthening G2/M phases to license transcriptional plasticity. Crucially, IRAK4 suppression also enhanced direct lineage conversion, boosting the efficiency and functional maturity of MEF-derived hepatocyte-like cells (iHeps) via elevated albumin/Cyp3a11 expression, glycogen storage, and detoxification capacity. These results establish IRAK4 as a druggable regulator that constrains cellular plasticity by coupling innate immune signaling to cell cycle control. Targeting IRAK4 refines reprogramming strategies to overcome somatic barriers, enhancing the generation of pluripotent and functional lineage-specific cells for regenerative applications.
2026-09-02 | GSE303072 | GEO
Project description:Chemical reprogramming of somatic cells into pluripotent or lineage-specific cells offers transformative potential for regenerative medicine but is limited by molecular barriers. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), a key innate immune kinase, as a previously unrecognized barrier to multi-lineage reprogramming. We discovered that pharmacological inhibition of IRAK4 potently enhances reprogramming of mouse embryonic fibroblasts (MEFs) through the chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, significantly increasing colony formation and expression of core XEN regulators (Sox17/Gata4/Sall4/Foxa2). Genetic knockdown of Irak4 similarly accelerated reprogramming, while its overexpression blocked cell fate transitions. Mechanistically, IRAK4 inhibition remodels cell cycle dynamics, shortening G0/G1 and lengthening G2/M phases to license transcriptional plasticity. Crucially, IRAK4 suppression also enhanced direct lineage conversion, boosting the efficiency and functional maturity of MEF-derived hepatocyte-like cells (iHeps) via elevated albumin/Cyp3a11 expression, glycogen storage, and detoxification capacity. These results establish IRAK4 as a druggable regulator that constrains cellular plasticity by coupling innate immune signaling to cell cycle control. Targeting IRAK4 refines reprogramming strategies to overcome somatic barriers, enhancing the generation of pluripotent and functional lineage-specific cells for regenerative applications.
2026-09-02 | GSE303071 | GEO